JP5793505B2 - Aminopyrimidine kinase inhibitors - Google Patents

Description

(Related application)
This application is a priority of US Provisional Application No. 61 / 289,685 filed on Dec. 23, 2009 and U.S. Provisional Application No. 61 / 324,481 filed on Apr. 15, 2010. Insist on the interests of.

  Casein kinase 1 (CK1) is an evolutionarily conserved serine that contains seven known members in vertebrates (CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). / The family of threonine kinases. CK1 contains a typical kinase domain followed by a C-terminal tail, which is involved in the regulation of CK1 localization, substrate selectivity and kinase activity. A myriad of proteins are phosphorylated by CK1, which is involved in a wide range of cellular functions, including vesicle migration, DNA damage repair, cell cycle progression, cytokinesis and circadian rhythm (Gross and Anderson (1998). Vielhaber and Virshup (2001); review by Knippschild et al. (2005)). In addition, members of the CK1 family (-α, -δ / ε and -γ) regulate the activity of major signaling pathways (eg, Wnt and Shh) through several mechanisms (Peters et. Al., 1999; Liu et.al., 2002; Price and Kalderon, 2002; Davidson et.al., 2005; review by Zeng et.al., 2005, and Price (2006)).

In mammals, seven CK1 isoforms have been described: CK1α, β, γ _1-3 , δ and ε, and several splice variants. These all contain a highly conserved kinase domain, a short N-terminal domain of 6-76 amino acids and a highly variable C-terminal domain of more than 24-200 amino acids. The constitutive phosphotransferase activity of the CK1 isoform is tightly controlled by several mechanisms. For example, the closely related isoforms CK1δ and ε share 98% identity at the amino acid level in their catalytic domains, but are regulated by autophosphorylation, dephosphorylation and proteolytic cleavage. Members of the CK1 family are found in the nucleus, cytoplasm and plasma membrane. By phosphorylation of various substrates with either standard or non-standard consensus sequences, these can be found in many cells such as cell differentiation, cell proliferation, cell death, circadian rhythms, chromosome segregation, and vesicular transport. Modulates the activity of key regulatory proteins involved in the process.

  The Pim kinase family includes three isoforms, Pim-1, Pim-2 and Pim-3, and has recently emerged as an interesting target in oncology and immunomodulation. Ongoing research has functionally and mechanistically identified a role for these proteins in cell survival and proliferation, and overexpression has been observed in many human cancers and inflammatory conditions.

  Pim kinase suppresses cell death and regulates cell cycle progression. High levels of Pim kinase have been reported in solid tumors such as prostate cancer and pancreatic cancer. Pim-1 was first discovered in murine leukemia and several independent studies have shown that this kinase is upregulated in human prostate cancer. Pim-1, 2, and 3 build a distinct and highly homologous family of serine / threonine kinases that belong to the calmodulin-dependent protein kinase-related (CAMK) family. In addition to the three gene-encoded proteins, translational variants have also been reported for Pim-1 and 2 due to the use of alternative start codons. The name Pim refers to the first identification of the pim-1 gene as a frequent proviral insertion site in T-cell lymphoma induced by Moloney murine leukemia virus and subsequently encodes Pim-2 The gene was found to have similar susceptibility. Kinase (KID) -1 induced by depolarization and the originally designated Pim-3 were subsequently renamed due to high sequence similarity to Pim-1 (71% identity at the amino acid level). Considering all three isoforms, Pim protein is widely expressed at high levels in hematopoietic tissues and abnormally expressed in various human malignancies. Pim kinase promotes regulation of cell survival and proliferation, providing an opportunity for tumor treatment. Pim protein kinase is often overexpressed in prostate cancer and some forms of leukemia and lymphoma.

  A role for Pim kinase in immune regulation has also been observed. Pim-2 increases the level of expression in various inflammatory conditions and functions as a stimulatory regulator of interleukin 6 (IL-6), thereby stimulating the overexpression of kinase IL-6 levels Is reported to increase. Pim-1 and 2 are also implicated in cytokine-induced T cell growth and survival. Compared with Pim-1-/-Pim-2-/-mice to wild-type mice, the sensitivity of stimulated T cells after treatment with the immunosuppressant rapamycin increased the T cell activation to Pim-1. / Pim-2 deficiency was found to be significantly impaired, indicating that Pim kinase is a lymphocyte by PI3K / AKT (PKB, protein kinase B) / mammalian target in a pathway independent of rapamycin (mTOR) Suggests to promote growth and survival. In these pathways, overlapping parallel substrate specificities for other parallel but unrelated functions and proteins have also been reported and have implications for both inflammation and tumor, nuclear factor kappa-B (NF-κB) responsive genes Including transcriptional regulation of transcription. Pim kinase is therefore an attractive target for both therapeutic areas. Furthermore, Pim kinase has been reported to play a role in protecting the ATP binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) from proteolysis and proteasome degradation. Pgp is known to mediate drug efflux, so inhibitors of Pim kinase may provide a novel approach to cessation of drug resistance.

One aspect of the present invention relates to compounds that inhibit casein kinase 1 and / or casein kinase 2 and / or PIM kinase. For example, one embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[In the formula, independently for each occurrence,
W and X are independently oxygen or sulfur;
Z ¹ , Z ² and Z ³ are independently C—R ²⁰ or N, provided that at least one of Z ¹ and Z ² is N;
R ¹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, ^{-OR 8, -COR 8, -OP (} O) (oR 8) (oR 8), - P (O) (oR 8) (oR 8) and ^{-N (R 8) P (O} ) (oR 9) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, OR 16, O- [C (R 4) 2] p -R 5, NR 14 - [C (R ) _2] is selected from the group consisting of _p -R ⁵ and ^{SR 16;}
R ¹⁴ and R ¹⁵ are each hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,-[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ ,- _{^{C (O) oR 6, -SO}} 2 (R 6), - C (O) N (R 6) (R 7), - SO 2 N (R 6) (R 7), and -P (O) ( OR ⁶ ) (OR ⁷ ) independently selected; or R ¹⁴ and R ¹⁵ are joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]

One embodiment relates to a compound of formula 2, or a pharmaceutically acceptable salt thereof.

[In the formula, independently for each occurrence,
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, —OR ⁸ , —COR ⁸ , —OP (O) (OR ⁸ ) (OR ⁹ ), —P (O) (OR ⁸ ) (OR ⁹ ) and —N (R ⁸ ) P (O) (OR ⁹ ) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁶ and R ⁷ are optionally joined together, Forming a substituted heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, is selected from the group consisting of ^{oR 16,} and ^{SR 16; R 14} and R Each ⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, _{^{heterocyclylalkyl, - [C (R 4)}} 2] p -R 5, -COR 6, -C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), and —P (O) (OR ⁶ ) ( OR ⁷ ); independently selected from the group consisting of: OR ¹⁴ and R ¹⁵ joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]

One aspect of the present invention relates to a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.

One embodiment relates to any one of the aforementioned compounds, which is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment, the compound has an IC ₅₀ of less than 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment, the compound has an IC ₅₀ of less than 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment, the compound has an IC ₅₀ of less than 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

One embodiment relates to any one of the aforementioned compounds, which is an inhibitor of CK2. In one embodiment, the compound has an IC ₅₀ of less than 5000 nM for CK2. In one embodiment, the compound has an IC ₅₀ of less than 1000 nM for CK2. In one embodiment, the compound has an IC ₅₀ of less than 500 nM for CK2.

One embodiment relates to any one of the aforementioned compounds that is an inhibitor of PIM1, PIM2, or PIM3. In one embodiment, the compound has an IC ₅₀ of less than 5000 nM for PIM1, PIM2, or PIM3. In one embodiment, the compound has an IC ₅₀ of less than 1000 nM for PIM1, PIM2, or PIM3. In one embodiment, the compound has an IC ₅₀ of less than 500 nM for PIM1, PIM2, or PIM3.

  One embodiment relates to any one of the aforementioned compounds that is an inhibitor of the Wnt pathway.

  One embodiment relates to any one of the aforementioned compounds that is an inhibitor of the TGFβ pathway.

  One embodiment relates to any one of the aforementioned compounds that is an inhibitor of the JAK / STAT pathway.

  One embodiment relates to any one of the aforementioned compounds that is an inhibitor of the mTOR pathway.

  One embodiment relates to any one of the aforementioned compounds that is a modulator of Pgp degradation, drug efflux, or drug resistance.

  One embodiment relates to a pharmaceutical composition comprising any one or combination of the aforementioned compounds and a pharmaceutically acceptable carrier.

  Another embodiment relates to a method of inhibiting CK1 activity comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment is directed to a method of inhibiting CK1 activity comprising contacting CK2 with any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to abnormal CK1, CK1γ1, CK1γ2, or CK1γ3 activity comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions It relates to a method for treating or preventing a symptom.

  Another embodiment treats or prevents a condition associated with abnormal CK2 activity comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. Regarding the method.

  Another embodiment is directed to a method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. In one embodiment, the cancer is a cancer of a system selected from the group consisting of hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urinary system. In one embodiment, the cancer is mammalian bone marrow tissue, lymphoid tissue, pancreatic tissue, thyroid tissue, lung tissue, large intestine tissue, rectal tissue, anal tissue, liver tissue, skin, bone, ovarian tissue, uterine tissue, cervical tissue. Located in the breast, prostate, testicular tissue, brain, brainstem, meningeal tissue, kidney or bladder. In one embodiment, the cancer is breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, hematological malignancy, renal cell carcinoma, kidney cancer, melanoma, pancreatic cancer, lung cancer, Selected from the group consisting of colorectal cancer, brain tumor, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.

  Another embodiment relates to a method of treating leukemia or other hematological malignancies comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. .

  Another embodiment is directed to a method of treating Alzheimer's disease comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of treating a Wnt-dependent disease comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of treating a TGFβ-dependent disease comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of treating a JAK / STAT dependent disease comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of treating mTOR dependent diseases comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment includes administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions, inflammation, inflammatory diseases (eg, osteoarthritis and rheumatoid arthritis) ), Neurological symptoms (eg, Alzheimer's disease) and methods of treating or preventing neurodegeneration.

  Another embodiment treats bone related diseases and conditions, including osteoporosis and osteogenesis, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. Or it relates to a method of preventing or facilitating bone restoration.

  Another embodiment treats or prevents hypoglycemia, metabolic syndrome and diabetes comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. Regarding the method.

  Another embodiment comprises administering a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions to a mammal in need thereof, cell death (eg, the rate of cell death in cancer cells). To affect).

  Another embodiment relates to a method of treating or preventing abnormal embryonic development comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of inhibiting PIM activity comprising contacting PIM1, PIM2 or PIM3 with any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment treats or prevents a condition associated with abnormal PIM activity comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. Regarding the method.

  Another embodiment relates to a method of modulating Pgp degradation and / or drug efflux activity comprising contacting a cell with any one of the aforementioned compounds or pharmaceutical compositions.

  Another embodiment relates to a method of treating a malignancy based on modulation of Pgp comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment is a method of treating a malignancy based on modulation of Pgp, wherein a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions is administered to a mammal in need thereof. And in combination with another drug, compound or substance to stop resistance to that drug, compound or substance.
For example, the present invention provides the following items.
(Item 1)
A compound of formula 1 or a pharmaceutically acceptable salt thereof.


[In the formula, independently for each occurrence,
W and X are independently oxygen or sulfur;
Z ¹ , Z ² and Z ³ are independently C—R ²⁰ or N, provided that at least one of Z ¹ and Z ² is N;
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, ^{-OR 8, -COR 8, -OP (} O) (oR 8) (oR 8), - P (O) (oR 8) (oR 8) and ^{-N (R 8) P (O} ) (oR 9) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, OR 16, O- [C (R 4) 2] p -R 5, NR 14 - [C (R ) _2] is selected from the group consisting of _p -R ⁵ and ^{SR 16;}
R ¹⁴ and R ¹⁵ are each hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,-[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ ,- _{^{C (O) oR 6, -SO}} 2 (R 6), - C (O) N (R 6) (R 7), - SO 2 N (R 6) (R 7), and -P (O) ( OR ⁶ ) (OR ⁷ ) independently selected; or R ¹⁴ and R ¹⁵ are joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]
(Item 2)
Item 2. The compound according to Item 1, wherein W and X are oxygen.
(Item 3)
The compound according to item 1, wherein Z ¹ and Z ² are nitrogen; and Z ³ is C—R ²⁰ .
(Item 4)
Item 2. The compound according to item 1, wherein Z ¹ , Z ² and Z ³ are nitrogen.
(Item 5)
The compound according to item 1, wherein Z ¹ is nitrogen, and Z ² and Z ³ are each C—R ²⁰ .
(Item 6)
Z ² is is nitrogen; and, ^{Z 1} and ^{Z 3} is ^{C-R 20,} respectively, compound of claim 1.
(Item 7)
Item 2. The compound according to item 1, wherein R ¹ is hydrogen.
(Item 8)
The compound according to item 1, wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and — [C (R ⁴ ) ₂ ] _p —R ⁵ .
(Item 9)
The compound according to item 1, wherein W and X are oxygen, Z ¹ and Z ² are each nitrogen, Z ³ is —CR ²⁰ and R ¹ is hydrogen.
(Item 10)
R ² and R ³ are joined together, when forming a heterocyclic ring substituted by A compound according to any one of items 1-9.
(Item 11)
11. The compound according to item 10, wherein the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl.
(Item 12)
R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ) and —SO ₂ N (R ⁶ ) (R ⁷ ), independently selected from alkyl, alkenyl, 10. A compound according to any one of items 1 to 9, wherein alkynyl, aryl, heteroaryl, and heterocyclyl are optionally substituted.
(Item 13)
R ² is — [C (R ⁴ ) ₂ ] _p —R ⁵ , and R ³ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ) and —SO ₂ N (R ⁶ ) (R ⁷ ), wherein alkyl, alkenyl, alkynyl, aryl 13. A compound according to item 12, wherein heteroaryl and heterocyclyl are optionally substituted.
(Item 14)
14. The compound according to item 13, wherein R ⁵ is aryl or heteroaryl, each optionally substituted.
(Item 15)
14. The compound according to item 13, wherein R ⁵ is —N (R ⁸ ) (R ⁹ ).
(Item 16)
14. The compound according to item 13, wherein R ⁴ is hydrogen.
(Item 17)
R ²⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, trifluoromethyl, carboxyl, alkoxycarbonyl, acyl, nitro, amide, acylamino, sulfonamide, — [C (R ⁴ ) ₂ ] _{^{p -R 5; NR 14 R 15}} , oR 16, and is selected from the group consisting of ^{SR 16,} compound of claim 1, 3, 5 or 6.
(Item 18)
7. A compound according to item 1, 3, 5 or 6 wherein R ²⁰ is hydrogen.
(Item 19)
A compound of formula 2 or a pharmaceutically acceptable salt thereof.


[In the formula, independently for each occurrence,
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, —OR ⁸ , —COR ⁸ , —OP (O) (OR ⁸ ) (OR ⁹ ), —P (O) (OR ⁸ ) (OR ⁹ ) and —N (R ⁸ ) P (O) (OR ⁹ ) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁶ and R ⁷ are optionally joined together, Forming a substituted heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, is selected from the group consisting of ^{oR 16,} and ^{SR 16; R 14} and R Each ⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, _{^{heterocyclylalkyl, - [C (R 4)}} 2] p -R 5, -COR 6, -C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), and —P (O) (OR ⁶ ) ( OR ⁷ ); independently selected from the group consisting of: OR ¹⁴ and R ¹⁵ joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]
(Item 20)
20. A compound according to item 19, wherein R ¹ is hydrogen.
(Item 21)
R ²⁰ is a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, trifluoromethyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , NR ¹⁴ R ¹⁵ , OR ¹⁶ , and SR ^16. Selected from;
21. The compound according to item 19 or 20, wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl is optionally substituted.
(Item 22)
Item 21. The compound according to item 19 or 20, wherein R ²⁰ is hydrogen.
(Item 23)
23. A compound according to any one of items 19 to 22, wherein R ² and R ³ are joined together to form an optionally substituted heterocyclic ring.
(Item 24)
R ² and R ³ are joined together and

24. A compound according to item 23, forming an optionally substituted heterocyclic ring selected from the group consisting of
[In the formula, independently for each occurrence,
R ¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, _{^{heterocyclylalkyl, - [C (R 4)}} 2] p -R 5, -COR 12, -C (O) OR ¹² , —SO ₂ (R ¹² ), —C (O) N (R ¹² ) (R ¹³ ), —SO ₂ N (R ¹² ) (R ¹³ ), and —P (O) (OR ¹² ) ( Selected from the group consisting of OR ¹³ );
R ¹² and R ¹³ are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ¹² and R ¹³ are joined together Forming a heterocyclic ring;
R ¹¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N (R ¹⁷ ) (R ¹⁸ ), ^{-N (R 17) COR 18,} -N (R 17) C (O) OR 18, -N (R 17) SO 2 (R 18), - CON (R 17) (R 18), - OC (O ) N (R ¹⁷ )-(R ¹⁸ ), —SO ₂ N (R ¹⁷ ) (R ¹⁸ ), —OC (O) OR ¹⁷ , —COOR ¹⁷ , —C (O) N (OH) (R ¹⁷ ) _{^{, -OS (O) 2 OR 17}} , -S (O) 2 OR 17, -S (O) 2 R 17, -OR 17, -COR 17, -OP (O) (OR 17) (OR 18), -P (O ^{(OR 17) (OR 18)} , - N (R 17) P (O) (OR 18) (OR 18), and _{^{- [C (R 4) 2}} ] is selected from the group consisting of p -R ^5;
R ¹⁷ and ^{R 18} are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, selected from heteroaralkyl, and heterocyclylalkyl or Ranaru group; ^{or, R 17} and ^{R 18} are coupled together To form a heterocyclic ring; and
n is 0, 1, 2 or 3;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]
(Item 25)
R ¹⁰ is hydrogen, alkyl, aryl, heteroaryl, ^{heterocyclyl,} - from _{^{[C (R 4) 2]}} p -R 5, -COR 12, -C (O) OR 12, and _-SO 2 ^{(R 12)} Selected from the group consisting of:
25. A compound according to item 24, wherein any one of the aforementioned alkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted.
(Item 26)
25. A compound according to item 24, wherein n is 0.
(Item 27)
25. A compound according to item 24, wherein n is 1.
(Item 28)
R ¹¹ is alkyl, heterocyclyl, cyano, hydroxyalkyl, —N (R ¹⁷ ) (R ¹⁸ ), —CON (R ¹⁷ ) (R ¹⁸ ), and — [C (R ⁴ ) ₂ ] _p —R ^5. Selected from the group consisting of:
A compound according to item 27, wherein any of the aforementioned alkyls and heterocyclyls are optionally substituted.
(Item 29)
R ² and R ³ are joined together to form the formula:


25. The compound of item 24, wherein the compound forms an optionally substituted heterocyclic ring.
(Item 30)
30. The compound according to item 29, wherein n is 0 or 1.
(Item 31)
R ² and R ³ are joined together to form the formula:

25. The compound of item 24, wherein the compound forms an optionally substituted heterocyclic ring.
(Item 32)
R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), and —SO ₂ N (R ⁶ ) (R ⁷ ),
21. The compound according to item 19 or 20, wherein any of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl may be optionally substituted.
(Item 33)
33. The compound according to item 32, wherein R ³ is — [C (R ⁴ ) ₂ ] _p —R ⁵ .
(Item 34)
34. A compound according to item 33, wherein R ² is optionally substituted alkyl.
(Item 35)
34. A compound according to item 33, wherein R ⁴ is hydrogen.
(Item 36)
34. The compound according to item 33, wherein R ⁴ is hydroxy.
(Item 37)
34. A compound according to item 33, wherein R ⁵ is aryl, heteroaryl, heterocyclyl, each optionally substituted.
(Item 38)
34. The compound according to item 33, wherein p is 1, 2 or 3.
(Item 39)
R ⁵ is —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ) SO ₂ (R ⁹ ), ^{-CON (R 8) (R 9} ), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC (O) OR 8, -COOR _{^{9, -C (O) N (}} OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, -OR 8, -COR 8 ^{, -OP (O) (oR 8} ) (oR 8), - consisting of ^{P (O) (oR 8)} (oR 8), and ^{-N (R 8) P (O} ) (oR 9) (oR 9) 34. A compound according to item 33, selected from the group.
(Item 40)
40. The compound according to item 39, wherein R ⁵ is —N (R ⁸ ) (R ⁹ ).
(Item 41)
A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.
(Item 42)
A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.
(Item 43)
43. The compound according to any one of items 1 to 42, which is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3.
(Item 44)
44. The compound of item 43, having an IC ₅₀ of less than 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.
(Item 45)
45. The compound of item 44, having an IC ₅₀ of less than 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.
(Item 46)
46. The compound of item 45, having an IC ₅₀ of less than 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.
(Item 47)
43. A compound according to any one of items 1-42, which is an inhibitor of CK2.
(Item 48)
48. Compound according to item 47, having an IC ₅₀ of less than 5000 nM for CK2.
(Item 49)
49. The compound of item 48, having an IC ₅₀ of less than 1000 nM for CK2.
(Item 50)
_50. The compound of item 49, having an IC ₅₀ of less than 500 nM for CK2.
(Item 51)
43. A compound according to any one of items 1-42, which is an inhibitor of PIM1, PIM2, or PIM3.
(Item 52)
52. The compound of item 51, having an IC ₅₀ of less than 5000 nM for PIM1, PIM2, or PIM3.
(Item 53)
53. The compound of item 52, having an IC ₅₀ of less than 1000 nM for PIM1, PIM2, or PIM3.
(Item 54)
54. Compound according to item 53, having an IC ₅₀ of less than 500 nM for PIM1, PIM2, or PIM3.
(Item 55)
43. A compound according to any one of items 1-42, which is an inhibitor of the Wnt pathway.
(Item 56)
43. A compound according to any one of items 1-42, which is an inhibitor of the TGF pathway.
(Item 57)
43. A compound according to any one of items 1-42, which is an inhibitor of the JAK / STAT pathway. (Item 58)
43. A compound according to any one of items 1-42, which is an inhibitor of the mTOR pathway.
(Item 59)
43. A compound according to any one of items 1-42, which is a regulator of Pgp degradation, drug efflux, or drug resistance.
(Item 60)
60. A pharmaceutical composition comprising the compound according to any one of items 1 to 59 and a pharmaceutically acceptable excipient.
(Item 61)
60. A method of inhibiting CK1 activity, comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with the compound according to any one of items 1 to 59 or the pharmaceutical composition according to item 60.
(Item 62)
60. A method of inhibiting CK2 activity comprising contacting CK2 with the compound according to any one of items 1 to 59 or the pharmaceutical composition according to item 60.
(Item 63)
60. A method of treating or preventing a symptom associated with abnormal CK1, CK1γ1, CK1γ2, or CK1γ3 activity, the compound according to any one of items 1 to 59, or the pharmaceutical composition according to item 60 Administering an effective amount to a mammal in need thereof.
(Item 64)
60. A method of treating or preventing a symptom associated with abnormal CK2 activity, comprising the therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. Administering to a mammal.
(Item 65)
60. A method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. Method.
(Item 66)
68. The method of item 65, wherein the cancer is a hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system or urinary system.
(Item 67)
Cancer is mammalian bone marrow tissue, lymphoid tissue, pancreatic tissue, thyroid tissue, lung tissue, colon tissue, rectal tissue, anal tissue, liver tissue, skin, bone, ovarian tissue, uterine tissue, cervical tissue, breast, prostate, 70. The method of item 66, located in testicular tissue, brain, brain stem, meningeal tissue, kidney or bladder.
(Item 68)
Cancer is breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, hematological malignancy, renal cell carcinoma, kidney cancer, melanoma, pancreatic cancer, lung cancer, colorectal cancer, brain tumor 68. A method according to item 67, which is a head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer or myelodysplastic syndrome.
(Item 69)
60. A method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. Including methods.
(Item 70)
60. A method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. A method involving that.
(Item 71)
60. A method for treating a TGFβ-dependent disease, wherein a therapeutically effective amount of the compound according to any one of items 1 to 59 or the pharmaceutical composition according to item 60 is administered to a mammal in need thereof. A method involving that.
(Item 72)
60. A method for treating a JAK / STAT-dependent disease, wherein a therapeutically effective amount of the compound according to any one of items 1 to 59 or the pharmaceutical composition according to item 60 is given to a mammal in need thereof. A method comprising administering.
(Item 73)
60. A method of treating an mTOR dependent disease, wherein a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60 is administered to a mammal in need thereof. A method involving that.
(Item 74)
60. Inflammation, inflammatory disease (for example, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60 , Osteoarthritis and rheumatoid arthritis), methods of treating or preventing neurological symptoms (eg Alzheimer's disease) and neurodegeneration.
(Item 75)
60. A bone comprising osteoporosis and osteogenesis comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. A method of treating or preventing related diseases and symptoms or facilitating bone restoration. (Item 76)
60. Administration of a therapeutically effective amount of a compound according to any one of items 1 to 59, or a pharmaceutical composition according to item 60 to a mammal in need thereof, hypoglycemia, metabolic syndrome and A method of treating or preventing diabetes.
(Item 77)
60. Effects on cell death comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59, or a pharmaceutical composition according to item 60 (e.g. To increase the rate of cell death in cancer cells).
(Item 78)
Treating abnormal embryonic development comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59, or a pharmaceutical composition according to item 60; or How to stop.
(Item 79)
60. A method of inhibiting PIM activity comprising contacting PIM1, PIM2 or PIM3 with a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60.
(Item 80)
Item 60. Associated with abnormal PIM activity comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60. How to treat or stop symptoms.
(Item 81)
A method of modulating Pgp degradation and / or drug efflux activity comprising contacting a cell with any one of the aforementioned compounds or pharmaceutical compositions.
(Item 82)
60. A malignancy based on modulation of Pgp comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60 How to treat.
(Item 83)
60. A method of treating a malignant tumor based on modulation of Pgp, wherein a therapeutically effective amount of a compound according to any one of items 1 to 59 or a pharmaceutical composition according to item 60 is provided. A method of stopping resistance to a drug, compound or substance in combination with another drug, compound or substance, comprising administering to an animal.

10 is a graph depicting the relative activity of CK1γ1 (h) as a function of compound 4981 concentration. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of compound 4981 concentration. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of Compound 4981. 10 is a graph depicting the relative activity of CK1δ (h) as a function of compound 4981 concentration. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4981 concentration. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of Compound 4993. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of the concentration of Compound 4993. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of Compound 4993. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of Compound 4993. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4993 concentration. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of compound 4991. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of the concentration of Compound 4991. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of compound 4991. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of compound 4991. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4991 concentration. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of Compound 4999. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of the concentration of Compound 4999. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of Compound 4999. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of Compound 4999. 10 is a graph depicting the relative activity of CK1 (y) as a function of the concentration of Compound 4999. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of Compound 4985. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of compound 4985 concentration. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of Compound 4985. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of Compound 4985. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4985 concentration. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of compound 4992. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of compound 4992 concentration. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of compound 4992 concentration. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of compound 4992. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4992 concentration. 10 is a graph depicting the relative activity of CK1γ1 (h) as a function of the concentration of Compound 4996. 10 is a graph depicting the relative activity of CK1γ2 (h) as a function of the concentration of Compound 4996. 10 is a graph depicting the relative activity of CK1γ3 (h) as a function of the concentration of Compound 4996. 10 is a graph depicting the relative activity of CK1δ (h) as a function of the concentration of Compound 4996. 10 is a graph depicting the relative activity of CK1 (y) as a function of compound 4996 concentration. 3 is a graph depicting the relative activity of CK1γ1 (h) as a function of compound 5000 concentration. 3 is a graph depicting the relative activity of CK1γ2 (h) as a function of compound 5000 concentration. 3 is a graph depicting the relative activity of CK1γ3 (h) as a function of compound 5000 concentration. 2 is a graph depicting the relative activity of CK1δ (h) as a function of compound 5000 concentration. 2 is a graph depicting the relative activity of CK1 (y) as a function of compound 5000 concentration. FIG. ₅ is a graph depicting gemcitabine dose response curves and EC ₅₀ for PC-3 cells, whose data serve as experimental controls. FIG. ₅ is a graph depicting gemcitabine dose response curves and EC ₅₀ for OVCAR-3 cells whose data serve as experimental controls. FIG. 7 is a graph depicting gemcitabine dose response curves and EC ₅₀ for LNCaP cells, whose data serve as experimental controls. FIG. ₅ is a graph depicting gemcitabine dose response curves and EC ₅₀ for Jurkat cells, whose data serve as experimental controls. FIG. 6 is a graph depicting gemcitabine dose response curves and EC ₅₀ for MDA-MB-468 cells, whose data serve as experimental controls. FIG. ₅ is a graph depicting gemcitabine dose response curves and IC ₅₀ for HCT116 cells whose data serve as experimental controls. FIG. 7 is a graph depicting gemcitabine dose response curves and IC ₅₀ for A549 cells, whose data serve as experimental controls. FIG. ₅ is a graph depicting gemcitabine dose response curves and IC ₅₀ for DU145 cells, whose data serve as experimental controls. FIG. 6 is a graph depicting the dose response curve and IC ₅₀ of sorafenib against HC1954 cells whose data serve as experimental controls. FIG. 7 is a graph depicting the dose response curve and EC ₅₀ of sorafenib against Caco-2 cells, whose data serve as experimental controls. FIG. 10 is a graph depicting the dose response curve and IC ₅₀ of compound 4991 against OVCAR-3 cells compared to cisplatin, whose data serve as experimental controls. FIG. 10 depicts a dose response curve and IC ₅₀ of compound 4991 against OVCAR-8 cells compared to cisplatin. FIG. 10 depicts a dose response curve and IC ₅₀ of compound 4991 against SK-OV-3 cells compared to cisplatin.

Definitions The definitions of terms used herein are intended to incorporate the current state-of-the-art definitions recognized for each term in the chemical and pharmaceutical fields. Illustrations are provided where appropriate. Unless otherwise limited to specific cases, individually or as part of a larger group, these definitions apply to terms used throughout this specification.

  If stereochemistry is not specifically indicated, all stereoisomers of the compounds of the invention are included within the scope of the invention as pure compounds as well as mixtures thereof. Unless otherwise noted, all individual enantiomers, diastereomers, geometric isomers, and combinations and mixtures thereof are encompassed by the present invention. Polymorphic crystal forms and solvates are also encompassed within the scope of the present invention.

  As used herein, the term “isolated” in reference to a compound of the invention means that the compound is not in a cell or tissue and the compound is usually part or all of the elements that normally accompany it. It means that it is separated from.

  As used herein, the term “pure” in reference to an isolated sample of a compound of the present invention means that the isolated sample contains at least 60% by weight of the compound. Preferably, the isolated sample contains at least 70% by weight of the compound. More preferably, the isolated sample contains at least 80% by weight of the compound. More preferably, the isolated sample contains at least 90% by weight of the compound. Most preferably, the isolated sample contains at least 95% by weight of the compound. The purity of an isolated sample of a compound of the invention can be assessed by a number of methods or combinations thereof; eg, thin layer, preparative or flash chromatography, mass spectrometry, HPLC, NMR analysis, and the like.

  The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art recognized and includes saturated fatty acids including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Includes group. In certain embodiments, a straight chain or branched alkyl has about 30 or less (eg, C ₁ -C ₃₀ for straight chain, C ₃ -C ₃₀ for branched chain) in its backbone, alternatively about 20 or less. Of carbon atoms. Similarly, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure and, alternatively, about 5, 6 or 7 carbons in the ring structure.

  If the number of carbons is not otherwise specified, “lower alkyl” refers to an alkyl group as defined above, except that the backbone structure has from 1 to about 10 carbons, alternatively from 1 to about 6 carbon atoms. Point to. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths.

  The term “aralkyl” is art-recognized and refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

  The terms “alkenyl” and “alkynyl” are art-recognized and are unsaturated aliphatic groups similar in length and possible substitution to the above alkyls, except that each contains at least one double or triple bond. Point to.

The term “aryl” is art-recognized and includes, for example, zeros such as benzene, naphthalene, anthracenepyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. Refers to five, six and seven membered monocyclic aromatic groups which may contain from 1 to 4 heteroatoms. Aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics”. Aromatic rings may be substituted as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, It may be substituted at one or more ring positions with silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF ₃ , —CN, and the like. The term “aryl” is also a polycyclic ring system having two or more cyclic rings in which two or more carbons are shared by two adjacent rings (the ring is a “fused ring”). including. However, at least one of the rings is aromatic, for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl.

  The terms ortho, meta and para are recognized in the industry and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The term “heterocyclyl”, “heteroaryl”, or “heterocyclic group” is art-recognized and includes a 3 to about 10 membered ring structure, alternatively 3 to about 7 membered, wherein the ring structure contains 1-4 heteroatoms. Refers to the ring. The heterocycle may also be a polycycle. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, Indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, piperonyl, phenoxazine, phenoxazine , Pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine Lactones, azetidinones and pyrrolidinones, sultams, a lactam of sultones, and the like. A heterocyclic ring is a substituent as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl , Ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF ₃ , —CN, etc., may be substituted at one or more positions.

The term “optionally substituted” may include one or more hydrogens that may be replaced with substituents described herein including, but not limited to, for example, alkyl, cycloalkyl Refers to a chemical group such as aryl. Halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, Aldehydes, esters, heterocyclyl, aromatic or heteroaromatic moieties, —CF ₃ , —CN, and the like.

The term “polycyclyl” or “polycyclic group” is art-recognized, and two or more carbons are shared by two adjacent rings (the ring is a “fused ring”) Of the ring (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl). Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each ring of the polycycle is substituted as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, It may be substituted with silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF ₃ , —CN, and the like.

  The term “carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art recognized and refers to —NO ₂ . The term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I. The term “sulfhydryl” is art-recognized and refers to —SH. The term “hydroxyl” means —OH. The term “sulfonyl group” is art-recognized and refers to —SO ₂ ^— . “Halide” refers to the corresponding anion of a halogen, and “pseudohalide” has the definition set forth in “Advanced Inorganic Chemistry” on page 560 by Cotton and Wilkinson.

The terms “amine” and “amino” are art recognized and include unsubstituted and substituted amines such as the general formula:

[Wherein R50, R51 and R52 each independently represent hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R61, or R50 and R51 together with the N atom to which they are attached. To complete a heterocycle having 4 to 8 atoms in the ring structure; R61 represents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is zero or from 1 to 8 An integer in the range. ] Represents a portion that can be represented by In other embodiments, R50 and R51 (and, R52 optionally) each independently hydrogen, alkyl, alkenyl, or represents _{- (CH} 2) m -R61. Thus, the term “alkylamine” includes an amine group as defined above with a substituted or unsubstituted alkyl attached thereto. That is, at least one of R50 and R51 is an alkyl group.

The term “acylamino” is art recognized and has the general formula:

[Wherein, R50 is as defined above, and R54 represents hydrogen, alkyl, alkenyl, or — (CH ₂ ) _m —R61, wherein m and R61 are as defined above. ] Represents a portion that can be represented by

The term “amide” is recognized in the industry as an amino-substituted carbonyl and has the general formula:

[Wherein R50 and R51 are as defined above. ] Which can be represented by]. Certain embodiments of amides in the present invention do not include imides that may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur group attached thereto. In certain embodiments, an “alkylthio” moiety is 1 of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S— (CH ₂ ) _m —R61, wherein m and R61 are as defined above. Represented by one. Exemplary alkylthio groups include methylthio, ethylthio, and the like.

The term “carboxyl” is recognized in the industry and has the general formula:

Wherein, X50 is a bond or represents an oxygen or sulfur, also, R55 and R56 are hydrogen, alkyl, alkenyl, _- represents a _(CH 2) m -R61 or a pharmaceutically acceptable salt thereof , R56 represents hydrogen , alkyl, alkenyl or — (CH ₂ ) _m —R61 in which m and R61 are as defined above. ] Is included. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an “ester”. Where X50 is an oxygen and R55 is as defined above, that moiety is referred to herein as a carboxyl group, and particularly when R55 is hydrogen, the formula represents a “carboxylic acid”. Where X50 is oxygen and R56 is hydrogen, the formula represents “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiolcarbonyl” group. Where X50 is sulfur and R55 or R56 is not hydrogen, the formula represents a “thiol ester”. Where X50 is sulfur and R55 is hydrogen, the formula represents a “thiol carboxylic acid”. Where X50 is sulfur and R56 is hydrogen, the formula represents a “thiol formate”. On the other hand, when X50 is a bond and R55 is not hydrogen, the above formula represents a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an “aldehyde” group.

  The term “carbamoyl” refers to —O (C═O) NRR where R and R ′ are independently H, an aliphatic group, an aryl group, or a heteroaryl group.

  The term “oxo” refers to a carbonyl oxygen (═O).

The terms “oxime” and “oxime ether” are recognized in the industry and have the general formula:

[Wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or — (CH ₂ ) _m —R61. ] Represents a portion that can be represented by The moiety is an “oxime” when R is H. Also, when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or — (CH ₂ ) _m —R61, it is an “oxime ether”.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen group attached thereto. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is, -O- alkyl, -O- alkenyl, -O- alkynyl, m and R61 are as defined above -O _{- (CH} 2) m -R61 , Alkoxyl, or similar to alkoxyl, as may be represented by one of.

The term “sulfonate” is recognized in the industry and has the general formula:

[Wherein R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. ] Represents a portion that can be represented by The term “sulfate” is recognized in the industry and is a general formula wherein R57 is as defined above:

Includes a portion that can be represented by

The term “sulfonamide” is art recognized and has the general formula: R50 and R56 are as defined above.

Includes a portion that can be represented by

The term “sulfamoyl” is art recognized and has the general formula: R50 and R51 are as defined above.

Refers to the part that can be represented by.

The term “sulfonyl group” is recognized in the industry and has the general formula:

Wherein R58 is one of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. ] Represents a portion that can be represented by

The term “sulfoxide” is art-recognized and R58 is defined by the general formula:

Refers to the part that can be represented by.

The term “phosphoryl” is art recognized and generally has the formula:

[Wherein, Q50 represents S or O, and R59 represents hydrogen, lower alkyl or aryl. ]. For example, when used to substitute alkyl, the phosphoryl group of phosphorylalkyl has the general formula:

[Wherein Q50 and R59 are each independently defined above, and Q51 represents O, S or N.] ] May be represented. When Q50 is S, the phosphoryl moiety is “phosphorothioate”.

The term “phosphoramidite” is art recognized and has the general formula: Q51, R50, R51, and R59 are as defined above.

It can be expressed as

The term “phosphonamidite” is art-recognized and has the general formula: Q51, R50, R51 and R59 are as defined above, and R60 represents lower alkyl or aryl:

It can be expressed as

  Similar substitutions can be made on alkenyl and alkynyl groups to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl.

  The definition of each expression, such as alkyl, m, n, etc., is intended to be independent of its definition elsewhere in the same structure if it occurs multiple times in any structure.

  The terms trifuryl, tosyl, mesyl, and nonafryl are art recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl, respectively. The terms triflate, tosylate, mesylate, and nonaflate are recognized in the industry and include trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate, and nonafluorobutanesulfonate functional groups Refers to each containing molecule.

  The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, and methanesulfonyl, respectively. A further overview of the abbreviations used by organic chemists in the industry can be found in the first volume of the Journal of Organic Chemistry, which is typically titled “Standard List of Abbreviations.” Presented in the table.

  Certain compounds included in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention includes cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof. All such compounds are contemplated as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be encompassed by the present invention.

  For example, if a particular enantiomer of a compound of the invention is desired, the resulting diastereomeric mixture is separated by asymmetric synthesis or the resulting diastereomeric mixture and the auxiliary group provides the pure desired enantiomer It may be prepared by induction with a chiral auxiliary that is cleaved to do so. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, a diastereomeric salt with an appropriate optically active acid or base is formed, followed by fractionation well known in the art. Resolution of the diastereomers thus formed by means of crystallization or chromatography and recovery of the pure enantiomer follows.

  “Substituted” or “substituted with” results in compounds in which such substitution corresponds to the permissible valency of substituent atoms and substituents, and substitution is stable, eg, rearrangement, cyclization It will be understood that it includes the absolute requirement that no conversion occurs spontaneously, such as by elimination or other reactions.

  The term “substituted” is also intended to include all permissible substituents of organic compounds. In a wide range of embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described hereinabove. The permissible substituents may be the same or different for one or more and the appropriate organic compound. For purposes of the present invention, a heteroatom such as nitrogen can have a hydrogen substituent and / or any permissible substituent of the organic compounds described herein that meet the valence of the heteroatom. The present invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

As used herein, the phrase “protecting group” means a provisional substituent that protects a potentially reactive functional group from unwanted chemical changes. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and aldehyde and ketone ketals and acetals, respectively. Examples of nitrogen protecting groups include amide (—NRC (═O) R) or urethane (—NRC (═O) OR), for example as follows: As methylamide (NHC (= O) CH3); benzyloxyamide (NHC (= O) OCH2C6H5NHCbz); t-butoxyamide (NHC (= O) OC (CH3) 3, -NHBoc); 2-biphenyl-2-propoxy Amide (-NHC (= O) OC (CH3) 2C6H4C6H5NHBoc), 9-fluorenylmethoxyamide (-NHFmoc), 6-nitroveratryloxyamide (-NHNvoc), 2-trimethylsilylethyloxyamide (-NHTeoc) ) As 2,2,2-trichloroethyloxyamide (—NTRoc), as allyloxy group amide (—NHAlloc), as 2- (phenylsulfonyl) ethyloxyamide (—NHPsec); or as appropriate cases (eg, In cyclic amines) as nitroxide groups. The field of protecting group chemistry has been reviewed (Greene, T.W .; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed .; Wiley: New York, 1991). Protected forms of the compounds of the invention are included within the scope of the invention.

  The term “pharmaceutically acceptable salt” or “salt” refers to a salt of one or more compounds. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts such as those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and para- Toluenesulfonic acid, salicylic acid, tartaric acid, benzoic acid ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, shu Includes organic acids such as acids, para-bromophenyl sulfonic acid, carbonic acid, succinic acid, citric acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate Salt, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprate, acrylate, formate, isobutyrate, caprate, heptanoate, propiol Acid salt, oxalate salt, malonate salt, succinate salt, suberate salt, sebacate salt, fumarate salt, maleate salt, butyne-1,4-diionate, hexyne-1,6-diionate , Benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate terephthalate, sulfonate, xylenesulfo Acid salt, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, Naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

  Where the compound has one or more acidic moieties, pharmaceutically acceptable salts can be formed by treating a solution of the compound with a solution of a pharmaceutically acceptable base. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups are alkali metal hydroxides and carbonates such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; and Including, but not limited to, other metals such as aluminum and zinc. Suitable bases are also ammonia and organic amines such as unsubstituted or hydroxy substituted mono, di or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; Mono, bis or tris- (2-hydroxy-lower alkylamine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl) methylamine, N, N, such as bis or tris- (2-hydroxyethyl) amine N, N-dialkyl-N- (hydroxyalkyl) -amine, such as dimethyl-N- (2-hydroxyethyl) amine, or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and arginine Amycin such as lysine incllude containing an acid.

  Certain compounds of the present invention and their salts may exist in multiple crystalline forms (ie, polymorphs) and the present invention includes each of the crystalline forms and mixtures.

Certain compounds of the present invention and their salts may exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures.

  Certain compounds of the present invention contain one or more chiral centers and may exist in different optically active forms. When a compound of the present invention contains one chiral center, the compound exists in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof. Enantiomers may be resolved by methods known to those skilled in the art, for example, enantiomers may be separated by diastereoisomeric derivatives or complexes that may be separated by, for example, crystallization; for example, crystallization, gas-liquid or liquid chromatography. Formation; for example, selective reaction of one enantiomer with an enantiomer-specific reagent, eg, via esterification of the enzyme; or chiral environment, eg, a chiral support suitable include chiral supports (eg, with bound asymmetric ligands) Can be resolved by the formation of diastereomeric isomer salts which can be separated by gas-liquid or liquid chromatography in the presence of silica) or chiral solvents. If the desired enantiomer is converted to another chemical by one of the separation methods described above, additional steps may be used to release the desired purified enantiomer. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. .

  Where a compound of the invention contains multiple chiral centers, it can exist in diastereoisomeric forms. Diastereoisomeric compounds may be separated by methods known to those skilled in the art (eg chromatography or crystallization) and the individual enantiomers may be separated as described above. The present invention includes various diastereomers of the compounds of the present invention, and mixtures thereof. The compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the invention includes each tautomer and / or geometric isomer of a compound of the invention, and mixtures thereof . For example, any olefin present in a compound can exist as either the E or Z geometric isomer or a mixture thereof, unless otherwise specified. The compounds of the present invention may exist in the form of zwitterions. The present invention includes each zwitterionic form of the compounds of the invention and mixtures thereof.

  As used herein, the term “prodrug” refers to an agent that is converted to the parent drug in vivo by some physiological chemical process (eg, once the prodrug is at physiological pH, the desired Converted into drug form). Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. Prodrugs are available to the organism, for example, by oral administration, but not the parent drug. Prodrugs can also improve solubility in pharmaceutical compositions over the parent drug. A non-limiting example of a prodrug is that it is administered as an ester ("prodrug") to facilitate transmission across cell membranes where water solubility is not advantageous, but it is then advantageous for water solubility. It is a compound of the present invention when it is metabolically hydrolyzed to a carboxylic acid in a cell. Prodrugs have many useful properties. For example, prodrugs may be more water soluble than the final drug, thereby facilitating intravenous administration of the drug. Prodrugs can also have higher levels of oral bioavailability than the final drug. Following administration, the prodrug is cleaved enzymatically or chemically to deliver the final drug to the blood or tissue.

Exemplary prodrugs release amines of the compounds of the invention. Here, the free hydrogen of the amine or alcohol is (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1-methyl-1-((C ₁ -C ₆ ) Alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyl-oxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylamino-methyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄₎ alkanoyl, aryl activator Le and α- aminoacyl, or are replaced with α- aminoacyl -α- aminoacyl. However, the α-aminoacyl moiety is independently a naturally occurring L-amino acid found in proteins, —P (O) (OH) ₂ , —P (O) (O (C ₁ -C ₆ ). Alkyl) ₂ , or glycosyl (the group resulting from the removal of the hydroxyl of the carbohydrate hemiacetal).

Other exemplary prodrugs are cleaved to release the corresponding free acid. Residues forming such hydrolyzable esters of the compounds of the present invention are those wherein the free hydrogen is (C ₁ -C ₄ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, (C ₄ -C _9). ) 1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 4 to 7 carbon atoms Having 1- (alkoxycarbonyloxy) ethyl, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 4 to 1- (N- (alkoxycarbonyl) amino) ethyl having 10 carbon atoms, 3-phthalidyl, 4-crotonolactoni , Gamma - butyrolactone-4-yl, di _{-N, N- (C 1 -C 2} ) alkylamino _(C 2 -C ₃₎ alkyl, carbamoyl - _(C 1 -C ₂₎ alkyl, N, N-di ( C ₁ -C ₂₎ - alkylcarbamoyl - _(C 1 -C ₂₎ alkyl and piperidino -, pyrrolidino or morpholino _(C 2 -C ₃₎ are replaced by alkyl, carboxylic acid substituents (e.g., - (CH ₂ ) C (O) OH, a moiety containing a carboxylic acid), but is not limited thereto.

  The term “subject” as used herein refers to an animal, typically a mammal or a human, that has been or has been the purpose of treatment, observation, and / or experimentation. When the term was used in combination with administration of a compound or drug, the subject was for the purpose of treatment, observation, and / or administration of the compound or drug.

  The terms “co-administration” and “co-administering” refer to simultaneous administration (simultaneous administration of two or more therapeutic agents) and time-varying administration (additional) as long as the therapeutic agents are present to some extent simultaneously in the patient. Both the time of administration of the therapeutic agent (s) and the administration of one or more therapeutic agents at different times.

  As used herein, the term “therapeutically effective amount” refers to a cell culture, tissue as sought by a researcher, veterinarian, clinician or physician, including alleviation of the disease, condition or disorder being treated. The amount of active compound or drug that elicits a biological or medical response in a system, animal or human.

  The term “composition” is intended to encompass a product that includes a predetermined amount of a predetermined raw material, as well as any product that results directly or indirectly from a combination of a predetermined amount of a predetermined raw material.

The term “pharmaceutically acceptable carrier” refers to a medium that is used to prepare the desired dosage form of the compound. Pharmaceutically acceptable carriers include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surfactants; isotonic agents; thickeners or emulsifiers; Solid binders; lubricants and the like can be included. Remington's Pharmaceutical Sciences, Fifteenth Edition, E.M. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, A.M. H. Kibe ed. (American Pharmaceutical Assoc. 2000) discloses various carriers used to formulate pharmaceutical compositions and known techniques for their preparation.
Compound

One aspect of the present invention pertains to compounds of Formula 1 or pharmaceutically acceptable salts thereof.

[In the formula, independently for each occurrence,
W and X are independently oxygen or sulfur;
Z ¹ , Z ² and Z ³ are independently C—R ²⁰ or N, provided that at least one of Z ¹ and Z ² is N;
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, ^{-OR 8, -COR 8, -OP (} O) (oR 8) (oR 8), - P (O) (oR 8) (oR 8) and ^{-N (R 8) P (O} ) (oR 9) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, OR 16, O- [C (R 4) 2] p -R 5, NR 14 - [C (R ) _2] is selected from the group consisting of _p -R ⁵ and ^{SR 16;}
R ¹⁴ and R ¹⁵ are each hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,-[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ ,- _{^{C (O) oR 6, -SO}} 2 (R 6), - C (O) N (R 6) (R 7), - SO 2 N (R 6) (R 7), and -P (O) ( OR ⁶ ) (OR ⁷ ) independently selected; or R ¹⁴ and R ¹⁵ are joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]

  In one embodiment, W and X are oxygen.

In one embodiment, Z ¹ and Z ² are nitrogen; and Z ³ is C—R ²⁰ .

In one embodiment, Z ¹ , Z ² and Z ³ are nitrogen.

In one embodiment, Z ¹ is nitrogen; and Z ² and Z ³ are each C—R ²⁰ .

In one embodiment, Z ² is nitrogen; and Z ¹ and Z ³ are each C—R ²⁰ .

In one embodiment, R ¹ is hydrogen.

In one embodiment, R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and — [C (R ⁴ ) ₂ ] _p —R ⁵ .

In one embodiment, W and X are oxygen, Z ¹ and Z ² are each nitrogen, Z ³ is C—R ²⁰ and R ¹ is hydrogen.

In one embodiment, R ² and R ³ are joined together to form an optionally substituted heterocyclic ring.

  In one embodiment, the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl.

In one embodiment, R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O). Independently selected from the group consisting of OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), and —SO ₂ N (R ⁶ ) (R ⁷ ). Here, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R ² is — [C (R ⁴ ) ₂ ] _p —R ⁵ , and R ³ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —COR ⁶ , —C (O). Selected from the group consisting of OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), and —SO ₂ N (R ⁶ ) (R ⁷ ). Here, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R ⁵ is aryl or heteroaryl, each of which is optionally substituted.

In one embodiment, R ⁵ is —N (R ⁸ ) (R ⁹ ).

In one embodiment, R ⁴ is hydrogen.

In one embodiment, R ²⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, trifluoromethyl, carboxyl, alkoxycarbonyl, acyl, nitro, amide, acylamino, sulfonamide, — [C ( R ⁴ ) ₂ ] _p -R ⁵ ; selected from the group consisting of NR ¹⁴ R ¹⁵ , OR ¹⁶ , and SR ¹⁶ .

In one embodiment, R ²⁰ is hydrogen.

One aspect of the present invention pertains to compounds of Formula 2 or a pharmaceutically acceptable salt thereof.

[In the formula, independently for each occurrence,
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, —OR ⁸ , —COR ⁸ , —OP (O) (OR ⁸ ) (OR ⁹ ), —P (O) (OR ⁸ ) (OR ⁹ ) and —N (R ⁸ ) P (O) (OR ⁹ ) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁶ and R ⁷ are optionally joined together, Forming a substituted heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, oR 16, and is selected from the group consisting of ^{SR 16;}
R ¹⁴ and R ¹⁵ are each hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,-[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ ,- _{^{C (O) oR 6, -SO}} 2 (R 6), - C (O) N (R 6) (R 7), - SO 2 N (R 6) (R 7), and -P (O) ( OR ⁶ ) (OR ⁷ ) independently selected; or R ¹⁴ and R ¹⁵ are joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, -[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ , and -C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]

In one embodiment, R ¹ is hydrogen.

In one embodiment, R ²⁰ is hydrogen, alkyl, trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , NR ¹⁴ R ¹⁵ , OR ¹⁶ , and it is selected from the group consisting of ^{SR 16.}

In one embodiment, R ²⁰ is hydrogen.

In one embodiment, R ² and R ³ are joined together to form an optionally substituted heterocyclic ring.

In one embodiment, R ² and R ³ are joined together and

Forming an optionally substituted heterocyclic ring selected from the group consisting of
[In the formula, independently for each occurrence,
R ¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ¹² , —C (O) OR ¹² , —SO ₂ (R ¹² ), —C (O) N (R ¹² ) (R ¹³ ), —SO ₂ N (R ¹² ) (R ¹³ ), —P (O) (OR ¹² ) (OR ¹³ ) selected from the group consisting of;
R ¹² and R ¹³ are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ¹² and R ¹³ are joined together Forming a heterocyclic ring;
R ¹¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N (R ¹⁷ ) (R ¹⁸ ), ^{-N (R 17) COR 18,} -N (R 17) C (O) OR 18, -N (R 17) SO 2 (R 18), - CON (R 17) (R 18), - OC (O ) N (R ¹⁷ )-(R ¹⁸ ), —SO ₂ N (R ¹⁷ ) (R ¹⁸ ), —OC (O) OR ¹⁷ , —COOR ¹⁷ , —C (O) N (OH) (R ¹⁷ ) _{^{, -OS (O) 2 OR 17}} , -S (O) 2 OR 17, -S (O) 2 R 17, -OR 17, -COR 17, -OP (O) (OR 17) (OR 18), -P (O ^{(OR 17) (OR 18)} , - N (R 17) P (O) (OR 18) (OR 18), and _{^{- [C (R 4) 2}} ] is selected from the group consisting of p -R ^5;
R ¹⁷ and ^{R 18} are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, selected from heteroaralkyl, and heterocyclylalkyl or Ranaru group; ^{or, R 17} and ^{R 18} are coupled together To form a heterocyclic ring; and
n is 0, 1, 2 or 3;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]

In one embodiment, R ¹⁰ is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ¹² , —C (O) OR ¹² , and —SO ₂ ( R ¹² ) is selected from the group consisting of
Here, any one of the aforementioned alkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

  In one embodiment, n is 0.

  In one embodiment, n is 1.

In one embodiment, R ¹¹ is alkyl, heterocyclyl, cyano, hydroxyalkyl, —N (R ¹⁷ ) (R ¹⁸ ), —CON (R ¹⁷ ) (R ¹⁸ ), and — [C (R ⁴ ) ₂ ]. is selected from the group consisting of ^p -R ^5,
Here, any of the aforementioned alkyl and heterocyclyl may be optionally substituted.

In one embodiment, R ² and R ³ are joined together to form the formula:

To form an optionally substituted heterocyclic ring.

  In one embodiment, n is 0 or 1.

In one embodiment, R ² and R ³ are joined together to form the formula:
To form an optionally substituted heterocyclic ring.

In one embodiment, R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O). It is independently selected from the group consisting of OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), and —SO ₂ N (R ⁶ ) (R ⁷ ). Here, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R ³ is — [C (R ⁴ ) ₂ ] _p —R ⁵ .

In one embodiment, R ² is optionally substituted alkyl.

In one embodiment, R ⁴ is hydrogen.

In one embodiment, R ⁴ is hydroxy.

In one embodiment, R ⁵ is aryl, heteroaryl, heterocyclyl, each of which is optionally substituted.

In one embodiment, p is 1, 2 or 3.

In one embodiment, R ⁵ is —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ) SO _2. (R ⁹ ), —CON (R ⁸ ) (R ⁹ ), —OC (O) N (R ⁸ ) — (R ⁹ ), —SO ₂ N (R ⁸ ) (R ⁹ ), —OC (O) ^{OR 8, -COOR 9, -C (} O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, -OR ⁸ , —COR ⁸ , —OP (O) (OR ⁸ ) (OR ⁸ ), —P (O) (OR ⁸ ) (OR ⁸ ) and —N (R ⁸ ) P (O) (OR ⁹ ) (OR ⁹ ) ⁹ ) selected from the group consisting of:

In one embodiment, R ⁵ is —N (R ⁸ ) (R ⁹ ).

One embodiment of the present invention relates to a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

Any one of the foregoing compounds can exist as an E geometric isomer, a Z geometric isomer, or a mixture thereof. For example, in one embodiment, in the aforementioned structure

Represents the E isomer of a particular compound. In another embodiment,

Represents the Z isomer of a particular compound. In yet another embodiment,

Represents a mixture of E and Z isomers of a particular compound.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of CK1γ1, CK1γ2 or CK1γ3.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of the Wnt pathway.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of the JAK / STAT pathway.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of the mTOR pathway.

  In one embodiment, any one of the foregoing compounds is a modulator of Pgp degradation and / or drug efflux.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of the TGFβ pathway.

In some embodiments, the compound has an IC ₅₀ of less than 5000 nM for CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC ₅₀ of less than 1000 nM for CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC ₅₀ of less than 500 nM for CK1γ1, CK1γ2, or CK1γ3.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

In one embodiment, the compound has an IC ₅₀ of less than 5000 nM for CK2.

In one embodiment, the compound has an IC ₅₀ of less than 1000 nM for CK2.

In one embodiment, the compound has an IC ₅₀ of less than 500 nM for CK2.

  In one embodiment, any one of the aforementioned compounds is an inhibitor of PIM1, PIM2, or PIM3.

In one embodiment, the compound has an IC ₅₀ of less than 5000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC ₅₀ of less than 1000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC ₅₀ of less than 500 nM for PIM1, PIM2 or PIM3.

General synthetic scheme

The general synthetic scheme used to prepare the compounds disclosed in this application is described below. For example, the compounds of the invention can be prepared as shown in Scheme I.

Alternatively, the compounds of the invention can be prepared as shown in Scheme II.

Yet another method of making the compounds disclosed herein is depicted in Scheme III.
Theoretical embodiment

Certain compounds of the invention could be made by reacting an amine (Reactant A) with a hydantoin nucleus (Reactant B) according to the above scheme. Non-limiting theoretical examples of Reactant A and Reactant B are shown in Table 1 and Table 2, respectively.

Additional theoretical embodiments of the present invention can be performed using reactants A and B listed in Table 3 according to the above reaction scheme. The geometric isomers listed in Table 3 are believed to reflect the actual geometry of the theoretical compound when they are to be produced. However, final structural assignments can only be made when the compounds are synthesized and subjected to appropriate 2D NMR studies. Furthermore, although compounds are listed as “Z” geometric isomers, both E and Z geometric isomers and mixtures thereof are contemplated.

  Furthermore, it is convenient or desirable to prepare, purify, and / or handle the active compound in a chemically protected form. As used herein, the term “chemically protected form” refers to compounds in which one or more reactive functional groups are protected from undesired chemical reactions (ie, they are protecting groups). Qualified).

  By protecting the reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group. The protecting group can usually be removed in a subsequent step without substantially affecting the rest of the molecule. For example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; .

For example, a hydroxy group can be protected, for example, as an ether (—OR) or ester (—OC (═O) R) as follows: t-butyl ether; benzyl, benzhydryl (diphenylmethyl, or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyldimethylsilyl ether; or acetyl ester (—OC (═O) CH ₃ , —OAc).

For example, an aldehyde or ketone group can be protected as an acetal or ketal, respectively, and a carbonyl group (C (═O)) is converted to a diether (C (OR) ₂ ), for example, by reaction with a primary alcohol. Is done. Aldehyde or ketone groups are readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group can be protected, for example, as follows, for example, as an amide (—NRC (═O) R) or urethane (—NRC (═O) OR). Methylamide _{(NHC (= O) CH 3} ); benzyloxyamide _{(NHC (= O) OCH 2} C 6 H 5 NHCbz); t- butoxy amide _{(NHC (= O) OC (} CH 3) 3, -NHBoc) as ; as 2-biphenyl-2-propoxy amide _{(-NHC (= O) OC (} CH 3) 2 C 6 H 4 C 6 H 5 NHBoc), 9- fluorenyl methoxy amides (-NHFmoc), 6- Nitorobera Tolyloxyamide (—NHNvoc), as 2-trimethylsilylethyloxyamide (—NHTeoc), as 2,2,2-trichloroethyloxyamide (—NHTroc), as allyloxy group amide (—NHAlloc) as 2- ( As phenylsulfonyl) ethyloxyamide (-NHPsec); or Switching cases (e.g., cyclic amines) as the nitroxide groups in the.

  For example, a carboxylic acid group can be protected, for example, as an ester or amide as follows: Benzyl ester; t-butyl ester; methyl ester; or methylamide.

For example, a thiol group can be protected as, for example, the following thioether (—SR). Benzyl thioether; or acetamidomethyl ether (—SCH ₂ NHC (═O) CH ₃ ).
Pharmaceutical composition

  One or more compounds of the present invention, alone or in a pharmaceutical composition mixed with a suitable carrier or excipient, at a dose that treats or ameliorates a disease or condition described herein, It can be administered to a mammal. Mixtures of these compounds can also be administered to a patient as a simple mixture or in a suitable formulated pharmaceutical composition. For example, one aspect of the invention provides a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or It relates to a pharmaceutical composition comprising a carrier.

  Formulation and administration techniques for the compounds of this application are described in “Remington's Pharmaceutical Sciences,” Mack Publishing Co. , Easton, PA, latest edition, etc., can be found in references well known to those skilled in the art.

  Suitable routes of administration include, for example, oral, tear, rectal, oral mucosa, topical, or intestinal; intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraperitoneal, Parenteral delivery including intranasal or intraocular injection can be included.

  Alternatively, the compound may be administered locally rather than systemically, for example via injection of the compound directly into the edema site, often in a depot or sustained release formulation.

  Furthermore, the compound may be administered in a targeted drug delivery system, for example, in liposomes coated with endothelial cell specific antibodies.

  The pharmaceutical composition of the present invention can be produced, for example, by means of conventional mixing, dissolution, granulation, sugar-coated tablet production, fine powdering, emulsification, encapsulation, encapsulation or freeze-drying.

  Accordingly, a pharmaceutical composition for use according to the present invention comprises one or more excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable preparation in a conventional manner. Multiple physiologically acceptable carriers can be used to formulate. Proper formulation is dependent upon the route of administration chosen.

  For injection, the agents of the present invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological salt buffer. For oral mucosal administration, penetrants are used in formulations appropriate to the barrier to be permeated. Such penetrants are generally known in the art.

  For oral administration, the compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers formulate the compounds of this invention as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. for oral consumption by the patient being treated. Make it possible to do. Pharmaceutical preparations for oral use are obtained as a result of combining the solid excipients and the active compound after adding the appropriate auxiliaries as desired to obtain tablets or dragee cores. Can be obtained by grinding the mixture and processing the mixture of granules. Suitable excipients are lactose, sucrose, mannitol, or sorbitol; for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinyl Includes fillers such as sugars, including cellulose preparations such as pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

  Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. be able to. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

  Pharmaceutical preparations that can be used orally include push-fit capsules, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. Extruded capsules can contain the active ingredients in a mixture with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. . In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

  For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.

  For administration by inhalation, the compounds for use according to the present invention are pressure packs using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Alternatively, it is conveniently delivered in the form of an aerosol spray composition from a nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For use in an inhaler or insufflator, for example, gelatin capsules and cartridges may be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

  The compounds can be formulated for parenteral administration by infusion, eg, bulk injection, continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multidose containers supplemented with preservatives. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

  Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. In some cases, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

  Alternatively, the active ingredient may be in powder form for reconstitution prior to use with a suitable vehicle, eg, sterile pyrogen-free water.

  The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.

  In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds are formulated, for example, with suitable polymers or hydrophobic materials (eg, as an acceptable emulsion in oil) or ion exchange resins, or as poorly soluble derivatives (eg, as poorly soluble salts). May be.

  Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide dimethylsulfoxide may also be used. Additionally, the compounds may be delivered using sustained release systems such as semi-permeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained release capsules release the compound from several weeks up to over 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization may be used.

The pharmaceutical composition may also include a suitable solid or gel phase carrier, or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Method of treatment

  Provided herein are methods for modulating the activity of CK1 and its subtypes, CK2, Wnt pathway, and / or TGFβ pathway. Also provided herein are methods for treating or preventing symptoms and diseases whose course may be affected by modulation of the activity of CK1 (eg, CK1γ), CK2, Wnt pathway, and / or TGFβ pathway. . Such methods typically involve administering a therapeutically effective amount of a compound or composition of the invention to a subject in need thereof.

  Also provided herein are methods for modulating the activity of a PIM, such as PIM1, PIM2 or PIM3, JAK / STAT pathway, and / or mTOR pathway, and / or Pgp. There is also a method of treating or preventing symptoms and diseases whose course can be affected by modulation of the activity of PIM, such as PIM1, PIM2 or PIM3, JAK / STAT pathway, and / or mTOR pathway, and / or Pgp. Provided herein. Such methods typically involve administering a therapeutically effective amount of a compound or composition of the invention to a subject in need thereof.

  Various diseases such as cancer, inflammation, and inflammatory diseases (eg, osteoarthritis and rheumatoid arthritis), and neurological symptoms (eg, Alzheimer's disease) and neurodegeneration include CK1 (eg, CK1γ), CK2, Wnt pathway and It can be treated by administration of a modulator of the TGFβ pathway. Bone-related diseases and conditions, including osteoporosis and bone formation, can also be treated by administration of CK1 (eg, CK1γ), CK2, Wnt pathway and / or TGFβ pathway modulators. Bone repair can be facilitated by administration of a modulator of CK1 (eg, CK1γ), CK2, Wnt pathway and / or TGFβ pathway. Additional conditions that can be treated by administration of CK1 (eg, CK1γ), CK2, Wnt pathway and / or TGFβ pathway modulators include hypoglycemia, metabolic syndrome and diabetes. Modulators of CK1 (eg, CK1γ), CK2, Wnt pathway, and / or TGFβ pathway are also useful to affect cell death (eg, increase the rate of cell death of cancer cells). Modulators of CK1 (eg, CK1γ), CK2, Wnt pathway and / or TGFβ pathway are also useful for the treatment or prevention of abnormal embryonic development.

Based at least on the fact that increased CK1γ has been found to be associated with a particular cancer, a method of treating a subject's cancer comprises administering a therapeutically effective amount of a compound that inhibits CK1γ to a subject in need thereof Including doing. The PIM1, PIM2, PIM3, JAK / STAT pathway, and / or mTOR pathway has also been found to be associated with certain cancers. Accordingly, provided herein are methods for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits PIM1 and / or PIM2 and / or PIM3.

  PIM1, PIM2, and PIM3 are also related to Pgp protecting against degradation, which can regulate drug efflux and drug resistance. Accordingly, a therapeutically effective amount of a compound that inhibits PIM1 and / or PIM2 and / or PIM3 in combination with another drug, compound or substance that stops resistance to the drug, compound or substance is administered to a subject in need thereof Provided herein is a method of treating a malignant tumor comprising:

  The compounds described herein can generally be used to modulate cell proliferation. Thus, diseases that can be treated include hyperproliferative diseases such as benign and malignant cell growth.

  Exemplary cancers that can be treated include leukemias, eg, carcinomas such as acute lymphoid leukemia, myeloid leukemia, colorectal cancer and hepatocellular carcinoma. Other cancers are: acute lymphoblastic leukemia; acute lymphoblastic leukemia; acute myeloid leukemia; acute myeloid leukemia; adrenal cortex cancer, adrenocortical cancer; AIDS related cancer; AIDS related lymphoma; anal cancer; astrocytoma, childhood cerebellum Astrocytoma, childhood cerebrum; see basal cell carcinoma, skin cancer (non-melanoma); bile duct cancer, extrahepatic; bladder cancer; bladder cancer; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem nerve Brain tumor; brain tumor, brain stem glioma; brain tumor, cerebellar astrocytoma; brain tumor, cerebral astrocytoma / malignant glioma; brain tumor, ependymoma; brain tumor, medulloblastoma; brain tumor, not on tent Differentiated neuroectodermal tumor; brain tumor, visual pathway and hypothalamic glioma; brain tumor; breast cancer; breast cancer and pregnancy; breast cancer; breast cancer, male; bronchial adenoma / sigmoid carcinoma; Burkitt lymphoma; carcinoid tumor; carcinoid tumor, gastrointestinal ; Cancer of unknown primary tumor Central nervous system lymphoma, primary; cerebellar astrocytoma; cerebral astrocytoma / malignant glioma; cervical cancer; childhood cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorder; colon Cancer; colorectal cancer; cutaneous T cell lymphoma, mycosis fungoides and Cesar syndrome; endometrial cancer; ependymoma; esophageal cancer; esophageal cancer; Ewing family of tumors; extracranial germinoma; Extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; stomach (abdominal) cancer; gastric (abdominal) cancer; gastrointestinal carcinoid tumor; germ cell tumor, extracranial; embryo Ovarian germ cell tumor; trophoblastic tumor; glioma; glioma, childhood brain stem; glioma, childhood cerebral astrocytoma; glioma, childhood visual pathway and thalamus Lower part: hairy cell leukemia; head and neck cancer; blood (blood) cancer, hepatocellular (liver) cancer, Somatic (primary); hepatocellular (liver) cancer, childhood (primary); Hodgkin lymphoma; Hodgkin lymphoma; interpregnant Hodgkin lymphoma; hypopharyngeal cancer; hypothalamus and optic glioma; intraocular melanoma; Carcinoma (endocrine pancreas); Kaposi's sarcoma; kidney (renal cell) cancer; kidney cancer; laryngeal cancer; laryngeal cancer; leukemia, acute lymphoblasts; leukemia, acute lymphoblasts; Leukemia, loose lymphocytes; leukemia; myelocytic; leukemia, ciliary cells; lip and oral cancer; liver cancer, adult (primary); liver cancer, childhood (primary); lung cancer, non-small cell Lung cancer, small cells; lymphoma, AIDS-related; lymphoma, Burkitt; lymphoma, cutaneous T cells, mycosis fungoides and Cesar syndrome; lymphoma, Hodgkin; lymphoma, Hodgkin; lymphoma, interpregnancy Hodgkin; lymphoma, non-Ho Zymkin; lymphoma, non-Hodgkin; lymphoma, non-Hodgkin during pregnancy; lymphoma, primary central nervous system; macroglobulinemia, Waldenstrom; bone / osteosarcoma malignant fibrous histiocytoma; medulloblastoma; melanoma; Tumor, intraocular (eye); Merkel cell carcinoma; malignant mesothelioma, adult; mesothelioma; metastatic squamous cervical cancer of unknown primary; multiple endocrine adenomatosis; multiple myeloma / plasma cell neoplasm Myelodysplastic syndrome; myelodysplastic / myeloproliferative disorder; myeloid leukemia, chronic; myeloid leukemia, adult acute; myeloid leukemia, childhood acute; myeloma, multiple; myeloproliferative disorder, Chronic; nasal and sinus cancer; nasopharyngeal cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin lymphoma; non-Hodgkin lymphoma; non-Hodgkin lymphoma during pregnancy; non-small cell lung cancer; oral cancer; ; Osteosarcoma / bad bone Fibrohistiocytosis; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; low-grade ovarian tumor; pancreatic cancer; pancreatic islet cell; paranasal sinus and nasal cavity cancer; parathyroid cancer; Pseudoblastoma and undifferentiated neuroectodermal tumor on tent; pituitary tumor; plasma cell neoplasm / multiple myeloma; pulmonary pleuroblastoma; pregnancy and breast cancer; pregnancy and Hodgkin lymphoma; Hodgkin lymphoma; primary central nervous system lymphoma; prostate cancer; rectal cancer; renal cell (kidney) cancer; renal cell (kidney) cancer; renal pelvis, transitional cell cancer; retinoblastoma; rhabdomyosarcoma; salivary gland cancer; Sarcoma, Kaposi; Sarcoma, soft tissue; Sarcoma, soft tissue; Sarcoma, uterus; Cesar syndrome; Skin cancer (non-melanoma); Skin cancer; Skin cancer (melanoma); Skin cancer , Merkel cells; small cell lung cancer; Intestinal cancer; soft tissue sarcoma; soft tissue sarcoma; see squamous cell carcinoma, skin cancer (non-melanoma); squamous cell carcinoma of unknown primary, metastatic; abdominal (stomach) cancer; abdominal (stomach) cancer; Undifferentiated neuroectodermal tumors; see T-cell lymphoma, skin, mycosis fungoides and Cesar syndrome; testicular cancer; thymoma; thymoma and thymic carcinoma; thyroid cancer; thyroid cancer; Trophoblastic tumor, pregnancy; carcinoma of unknown primary site; cancer of unknown primary site; childhood abnormal cancer; ureter and kidney disc, transitional cell cancer; urethral cancer; uterine cancer, endometrium; uterus Includes sarcomas; vaginal cancer; visual pathway and hypothalamic glioma; vulvar cancer; Waldenstrom macroglobulinemia; Wilms tumor; and female cancer.

  Neurological diseases that can be treated include epilepsy, schizophrenia, bipolar disorder or other psychological and / or psychiatric disorders, neurological lesions, skeletal muscle decline, and neurodegenerative diseases such as neurodegenerative diseases. Exemplary neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. Another class of neurodegenerative diseases includes diseases caused at least in part by polyglutamine aggregation. This type of disease includes Huntington's disease, bulbar spinal muscular atrophy (SBMA or Kennedy disease), dentate nucleus red nucleus pallidal atrophy (DRPLA), spinocerebellar ataxia 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Macad-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12).

Wnt pathway, TGFβ pathway, JAK / STAT pathway, mTOR pathway, Pgp modulation, CK1, CK1γ, CK2, or other diseases in which PIM plays a role can be treated using the compounds and methods described herein or Can be prevented.
dose

  As used herein, a “therapeutically effective amount” or “therapeutically effective dose” completely or partially inhibits the progression of symptoms or at least partially alleviates one or more symptoms of the symptoms. The amount of a compound of the present invention or a combination of two or more such compounds. A therapeutically effective amount can also be a prophylactically effective amount. The therapeutically effective amount will depend on the patient's size and sex, the condition being treated, the severity of the condition and the desired result. For a given patient, the therapeutically effective amount can be determined by methods known in the art.

A therapeutically effective dose refers to that amount of the compound that results in recovery of the patient's symptoms. The toxicity and therapeutic efficacy of such compounds is determined, for example, by cell culture or standard pharmaceutical procedures in laboratory animals to determine maximum tolerated dose (MTD) and ED ₅₀ (effective dose for 50% maximal response). be able to. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED _50. Data obtained from these cell culture assays and animal studies can be used to formulate the range of doses used in humans. The dosage of such compounds is preferably within a range of blood concentrations, including the ED ₅₀ with little or no toxicity. Dosages can vary within this range depending on the dosage form used and the route of administration used. Individual physicians can select the exact formulation and route of administration and dosage in view of the patient's symptoms. In the treatment of acute onset, administration of an acute bolus or dip near MTD may be necessary to obtain a rapid response.

  Dosage and interval are CK1, CK1γ, CK2, Pim1-3, Wnt pathway, TGFβ pathway, JAK / STAT pathway, mTOR pathway, or active portion sufficient to maintain Pgp modulating effects or minimal effective concentration (MEC) Can be individually adjusted to give plasma levels of The MEC will vary for each compound but can be estimated from in vitro data. The dosage required to achieve MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

  Dosage intervals can also be determined using the MEC value. The compound is administered using a regimen that maintains plasma levels above the MEC for a period of 10-90%, preferably 30-90%, most preferably 50-90% until the desired recovery of symptoms is achieved. It should be. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of composition administered will, of course, depend on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
kit

The compounds and compositions of the present invention (eg, compounds and compositions of Formula I) can be provided in packs or dispenser devices that can include one or more unit dosage forms containing the active ingredients, if desired. . The pack may include a metal or plastic foil, such as a blister pack, for example. The pack or dispenser device may be accompanied by instructions for administration. A composition comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container and labeled for the treatment of the indicated condition. Instructions for use can also be provided.
Illustration

Although the present invention has been generally described herein, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention. And is not intended to limit the invention. Although the geometric isomers depicted below are believed to be accurate, final structure assignments are made by 2-D NMR studies. Although the exemplary compounds described below are believed to be Z geometric isomers, E geometric isomers and mixtures of E and Z isomers are also contemplated by this disclosure.

Example 1

(E) -4- (Dimethylamino) -1,1-dimethoxybut-3-en-2-one (1): 1,1-dimethoxy-N, N-dimethylmethanamine (100 g, 839 mmol, 1.02 Equivalent) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110 ° C. for 3 hours. The produced methanol was removed with a Dean-Stark instrument. After cooling the solution to room temperature, the remaining volatiles were removed in vacuo and 130 g of crude product (E) -4- (dimethylamino) -1,1-dimethoxybut-3-en-2-one (1) was obtained (130 g, theoretically 143 g, 91%). LC-MS m / z 283 (M + 1). Reference: WO2006 / 0097341A1, pg67.
Example 2

Sodium 4- (dimethoxymethyl) pyrimidine-2-thiolate (2): thiourea (64.7 g, 850 mmol, 1.13 eq), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 eq) A solution in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E) -4- (dimethylamino) -1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction was allowed to proceed at room temperature for 2 hours. Stir. The crude sodium 4- (dimethoxymethyl) pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m / z 209 (M + 1). Reference: WO2006 / 0097341A1, pg67.
Example 3

4- (Dimethoxymethyl) -2- (methylthio) pyrimidine (3): iodomethane (128 g, 902 mmol, 1.20 equiv) was added to sodium 4- (dimethoxymethyl) pyrimidine-2-thiolate (2) (156 g, 751 mmol). Was carefully added to a crude solution of in methanol (700 mL, 1.1 M) using a cooling ice-water bath to maintain the reaction temperature below 28 ° C. The resulting mixture was stirred at room temperature for 16 hours. After removing the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to give 4- (dimethoxymethyl) -2- (methylthio) pyrimidine (3 ) As a brown oil (53.7 g, theoretical 150 g, 35.7%). LC-MS m / z 201 (M + 1). Reference: WO2006 / 0097341A1, pg67.
Example 4

2- (Methylthio) pyrimidine-4-carbaldehyde (4): 4- (dimethoxymethyl) -2- (methylthio) pyrimidine (3) (53.7 g, 268 mmol) was added 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equivalent) and stirred at 60 ° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3 × 150 mL) and the combined organic layers were concentrated under reduced pressure to give 2- (methylthio) pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g). , Theoretically 41.5 g, 34%). LC-MS m / z 155 (M + 1). Reference: WO2006 / 009734A1, pg67.
Example 5

(Z) -5-((2- (methylthio) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (5): In a 40 mL round bottom vial, 2- (methylthio) pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv), and piperidine in ethanol (400 μL, 4 mmol, 0.8 equiv) (20 mL, 0.25 M). Loaded. The reaction mixture was heated to 80 ° C. and shaken for 20 hours. The resulting yellow precipitate was isolated by filtration, washed with ethanol (1 × 20 mL), dried in vacuo and (Z) -5-((2- (methylthio) pyrimidin-4-yl) Methylene) thiazolidine-2,4-dione (5) was obtained as a yellow solid (550 mg, theoretically 898 mg, 61%). LC-MS m / z 254 (M + 1).
Example 6

(Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (6): (Z) -5-((2- (methylthio) pyrimidine-4- Yl) methylene) thiazolidine-2,4-dione (5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was added to oxone (25.8 g, 41.5 mmol, 3 0.0 equiv) in water (175 mL). The resulting mixture was stirred at room temperature for 48 hours. The resulting precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL) to give (Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2. , 4-dione (6) was obtained as a solid (2.48 g, theoretical 3.94 g, 63%). LC-MS m / z 286 (M + 1).
Example 7

General Replacement Procedure 1: In a 2-drum round bottom vial, (Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (6) (25 mg, 0 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 eq) and the appropriate amine (0.0877 mmol, 1.0 eq) were charged. The reaction mixture was heated to 120 ° C. and shaken for 16 hours. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS triggered fraction collection) with acetonitrile / water gradient and trifluoroacetic acid as modifier. The pure fractions were then concentrated under reduced pressure (GenevacHT-4).
Example 8

(Z) -5-((2- (4- (Benzo [d] [1,3] dioxol-5-ylmethyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Was prepared using the general substitution procedure and 1- (benzo [d] [1,3] dioxol-5-ylmethyl) piperazine (16.6 mg, theoretical 37.4 mg, 44.3%). LC-MS m / z 426.5 (M + 1).
Example 9

(Z) -5-((2- (4- (p-Tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1- Prepared using (p-tolyl) piperazine (12.5 mg, theoretical 33.6 mg, 37.2%).
LC-MS m / z 382.5 (M + 1).
Example 10

(Z) -5-((2- (Methyl (2- (pyridin-2-yl) ethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure, and Prepared with N-methyl-2- (pyridin-2-yl) ethanamine (13.7 mg, theoretical 30 mg, 45.6%). LC-MS m / z 342.4 (M + 1).
Example 11

(Z) -5-((2- (4-Isopropylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced with a general substitution procedure and 1-isopropylpiperazine (15.3 mg, theoretical 29.3 mg, 52.1%). LC-MS m / z 334.4 (M + 1).
Example 12

(Z) -5-((2- (3,4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1 , 2,3,4-tetrahydroisoquinoline (0.1 mg, theoretical 29.8 mg, 0.3%). LC-MS m / z 339.4 (M + 1).
Example 13

(Z) -5-((2- (4- (pyridin-2-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1 Prepared with-(pyridin-2-yl) piperazine (25.7 mg, theoretical 32.4 mg, 79.3%). LC-MS m / z 369.4 (M + 1).
Example 14

(Z) -Methyl 1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) pyrrolidine-2-carboxylate was converted to the general substitution procedure and methylpyrrolidine-2 Prepared with carboxylate (3.1 mg, theoretical 29.4 mg, 10.5%). LC-MS m / z 335.4 (M + 1).
Example 15

(Z) -5-((2- (4-Methylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 1-methylpiperazine Prepared (0.1 mg, theoretically 26.9 mg, 0.4%). LC-MS m / z 306.4 (M + 1).
Example 16

(Z) -5-((2- (4-morpholinopiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 4- (piperidine-4 -Yl) Prepared with morpholine (14.7 mg, theoretical 33 mg, 44.5%). LC-MS m / z 376.4 (M + 1).
Example 17

(Z) -tert-butyl (1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) pyrrolidin-3-yl) carbamate is converted to a general substitution procedure, and Prepared using tert-butylpyrrolidin-3-ylcarbamate (0.1 mg, theoretical 34.4 mg, 0.3%). LC-MS m / z 392.4 (M + 1).
Example 18

(Z) -5-((2- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure, and 2 Prepared with-(piperazin-1-yl) pyrimidine (3.1 mg, theoretical 32.5 mg, 9.5%). LC-MS m / z 370.4 (M + 1).
Example 19

(Z) -5-((2-morpholinopyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and morpholine (7.8 mg, theoretically 25.7 mg. 30.3%). LC-MS m / z 293.3 (M + 1).
Example 20

(Z) -5-((2- (piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and piperidine (8.9 mg , Theoretically 25.5 mg, 34.8%). LC-MS m / z 291.3 (M + 1).
Example 21

(Z) -5-((2- (Pyrrolidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and pyrrolidine (8.3 mg , Theoretically 24.3 mg, 34.1%). LC-MS m / z 277.3 (M + 1).
Example 22

(Z) -5-((2- (4- (Pyrrolidin-1-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 4 Prepared with-(pyrrolidin-1-yl) piperidine (9.3 mg, theoretical 31.6 mg, 29.4%). LC-MS m / z 360.4 (M + 1).
Example 23

(Z) -tert-Butyl 4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperazine-1-carboxylate is converted to a general substitution procedure and tert- Prepared using butyl piperazine-1-carboxylate (6.7 mg, theoretical 34.4 mg, 19.5%). LC-MS m / z 392.4 (M + 1).
Example 24

(Z) -tert-butyl 4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) -1,4-diazepan-1-carboxylate Prepared using the substitution procedure and tert-butyl 1,4-diazepan-1-carboxylate (5.1 mg, theoretical 35.7 mg, 14.3%). LC-MS m / z 406.5 (M + 1).
Example 25

(Z) -5-((2- (4- (2-morpholino-2-oxoethyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure; And 1-morpholino-2- (piperazin-1-yl) ethanone (11.4 mg, theoretically 36.8 mg, 31%). LC-MS m / z 419.5 (M + 1).
Example 26

(Z) -5-((2- (4-Phenylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 1-phenylpiperazine Prepared (11.3 mg, theoretical 32.3 mg, 35%). LC-MS m / z 368.4 (M + 1).
Example 27

(Z) -5-((2- (methyl (phenethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, the general substitution procedure, and N-methyl-2-phenylethanamine Prepared. (8.3 mg, theoretical 30 mg, 27.7%) LC-MS m / z 341.4 (M + 1).
Example 28

(Z) -5-((2- (4- (Pyridin-4-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1 Prepared with-(pyridin-4-yl) piperazine (7 mg, theoretical 32.4 mg, 21.6%). LC-MS m / z 369.4 (M + 1).
Example 29

(Z) -tert-butyl (1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) carbamate is converted to a general substitution procedure, and Prepared using tert-butylpiperidin-4-ylcarbamate (5.9 mg, theoretical 35.7 mg, 16.5%). LC-MS m / z 406.5 (M + 1).
Example 30

(Z) -tert-butyl ((1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-3-yl) methyl) carbamate Prepared using the procedure and tert-butyl (piperidin-3-ylmethyl) carbamate (0.1 mg, theoretical 36.9 mg, 0.3%). LC-MS m / z 420.5 (M + 1).
Example 31

(Z) -5-((2- (4-Aminopiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted to the general substitution procedure and tert-butylpiperidin-4-yl Prepared using carbamate. The purified and boc protected product was then treated with dichloromethane (1.0 mL), hydrochloric acid in methanol (500 μL, 1.25 M) and shaken at 50 ° C. for 16 hours. The reaction mixture was then concentrated under reduced pressure (Genevac HT-4) to give (1.7 mg, 26.9 mg theoretical, 6.3%). LC-MS m / z 306.4 (M + 1).
Example 32

General Replacement Procedure 2: In a 2 drum round bottom vial, (Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (25 mg, 0.0877 mmol) , DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 eq) and the appropriate amine (0.0877 mmol, 1.0 eq) were charged. The reaction mixture was heated to 110 ° C. and shaken for 24 hours. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS triggered fraction collection) with acetonitrile / water gradient and trifluoroacetic acid as modifier. The pure fractions were then concentrated under reduced pressure (GenevacHT-4).
Example 33

(Z) -5-((2- (4-Benzoylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and phenyl (piperazin-1-yl ) Prepared with methanone (4.1 mg, theoretical 34.7 mg, 11.8%). LC-MS m / z 396 (M + 1).
Example 34

(R, Z) -5-((2- (4-Benzyl-3- (hydroxymethyl) -5-oxopiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and (R) -1-benzyl-6- (hydroxymethyl) piperazin-2-one (5.1 mg, theoretical 37.4 mg, 13.6%). LC-MS m / z 426 (M + 1).
Example 35

(Z) -N- (1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) pyrrolidin-3-yl) -N-ethylacetamide was substituted with Prepared using the procedure and N-ethyl-N- (pyrrolidin-3-yl) acetamide (12.1 mg, theoretical 31.8 mg, 38%). LC-MS m / z 362 (M + 1).
Example 36

(Z) -5-((2- (3- (dimethylamino) pyrrolidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and N, N- Prepared using dimethylpyrrolidin-3-amine (12.2 mg, theoretical 28.1 mg, 43.4%). LC-MS m / z 320 (M + 1).
Example 37

(Z) -5-((2- (Methyl (1-methylpyrrolidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and N, 1 Prepared with dimethylpyrrolidin-3-amine (1.1 mg, theoretical 28.1 mg, 3.9%). LC-MS m / z 320 (M + 1).
Example 38

(Z) -5-((2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 2- Prepared using (piperazin-1-yl) ethanol (4.4 mg, theoretical 29.5 mg, 14.9%). LC-MS m / z 336 (M + 1).
Example 39

(Z) -5-((2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 2- (piperazin-1-yl) -4- (trifluoromethyl) pyrimidine (5.8 mg, theoretical 38.5 mg, 15.1%). LC-MS m / z 438 (M + 1).
Example 40

(Z) -5-((2- (4- (4- (benzyloxy) phenyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure; And 1- (4- (benzyloxy) phenyl) piperazine (4 mg, theoretically 41.7 mg, 9.6%). LC-MS m / z 474 (M + 1).
Example 41

(Z) -5-((2- (4- (4-Chloro-2-fluorophenyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1- (4-chloro-2-fluorophenyl) piperazine (4.8 mg, theoretically 36.9 mg, 13%). LC-MS m / z 420 (M + 1).
Example 42

(Z) -5-((2- (4- (4- (tert-butyl) phenyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1- (4- (tert-butyl) phenyl) piperazine (3.7 mg, theoretical 37.2 mg, 10%). LC-MS m / z 424 (M + 1).
Example 43

(Z) -5-((2- (4- (3,5-bis (trifluoromethyl) phenyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 1- (3,5-bis (trifluoromethyl) phenyl) piperazine (3.8 mg, 44.3 mg theoretical, 8.6%). LC-MS m / z 504 (M + 1).
Example 44

(Z) -5-((2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) -1,4-diazepan-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general substitution procedure and 1- (4- (trifluoromethyl) pyrimidin-2-yl) -1,4-diazepane (4.9 mg, theoretical 39.7 mg, 12. 3%). LC-MS m / z 452 (M + 1).
Example 45

(Z) -5-((2- (4-([1,1′-biphenyl] -4-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 1-([1,1′-biphenyl] -4-yl) piperazine (1.2 mg, 39 mg theoretical, 3.1%). LC-MS m / z 444 (M + 1).
Example 46

(Z) -5-((2- (4- (Furan-2-carbonyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was synthesized according to the general substitution procedure, and furan Prepared using 2-yl (piperazin-1-yl) methanone (6 mg, theoretical 33.9 mg, 17.7%). LC-MS m / z 386 (M + 1).
Example 47

(Z) -5-((2- (4-((4-fluorophenyl) (phenyl) methyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using the displacement procedure and 1-((4-fluorophenyl) (phenyl) methyl) piperazine (14.4 mg, theoretical 41.8 mg, 34.4%). LC-MS m / z 476 (M + 1).
Example 48

(Z) -5-((2- (4- (Naphthalen-1-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1 Prepared with-(naphthalen-1-yl) piperazine (6.2 mg, theoretical 36.7 mg, 16.9%). LC-MS m / z 418 (M + 1).
Example 49

(Z) -5-((2- (4-([1,1′-biphenyl] -3-yl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general replacement procedure and 1-([1,1′-biphenyl] -3-yl) piperazine (10.4 mg, 39 mg theoretical, 26.7%). LC-MS m / z 444 (M + 1).
Example 50

(Z) -5-((2- (4-((4-fluorophenyl) sulfonyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure; And 1-((4-fluorophenyl) sulfonyl) piperazine (5.2 mg, theoretical 39.6 mg, 13.1%). LC-MS m / z 450 (M + 1).
Example 51

(Z) -1-tert-butyl 2-methyl 4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperazine-1,2-diborate And 1-tert-butyl 2-methylpiperazine-1,2-diborate (2.8 mg, theoretical 39.6 mg, 7%). LC-MS m / z 450 (M + 1).
Example 52

(Z) -5-((2- (4-Benzyl-3- (hydroxymethyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure, and Prepared using (1-benzylpiperazin-2-yl) methanol (1.7 mg, theoretical 36.2 mg, 4.7%). LC-MS m / z 413 (M + 1).
Example 53

(Z) -5-((2- (5-oxo-1,4-diazepan-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1, Prepared using 4-diazepan-5-one (1.1 mg, theoretical 28.1 mg, 3.9%). LC-MS m / z 320 (M + 1).
Example 54

(Z) -5-((2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution. Prepared using the procedure and 1- (4- (trifluoromethyl) phenyl) piperazine. LC-MS m / z 436 (M (3.3 mg, theoretical 38.3 mg, 8.6%) + 1).
Example 55

(Z) -5-((2- (4-Cyclohexylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 1-cyclohexylpiperazine Prepared (10.7 mg, theoretical 32.9 mg, 32.5%). LC-MS m / z 374 (M + 1).
Example 56

(Z) -5-((2- (Methyl (3- (piperidin-1-yl) propyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and N- Prepared using methyl-3- (piperidin-1-yl) propano-1-amine (10.2 mg, theoretical 31.8 mg, 32.1%). LC-MS m / z 362 (M + 1).
Example 57

(Z) -5-((2- (4-((1-methylpiperidin-4-yl) methyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general replacement procedure and 1-((1-methylpiperidin-4-yl) methyl) piperazine (7.3 mg, 42.3 mg theoretical, 17.2%). LC-MS m / z 403 (M + 1).
Example 58

(Z) -1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) -N- (2-hydroxyethyl) piperidine-4-carboxamide was replaced by general substitution. Prepared using the procedure and N- (2-hydroxyethyl) piperidine-4-carboxamide (10.8 mg, theoretical 39.7 mg, 27.2%). LC-MS m / z 378 (M + 1).
Example 59

(Z) -5-((2- (4- (4-Methylpiperazin-1-carbonyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And (4-methylpiperazin-1-yl) (piperidin-4-yl) methanone (5.5 mg, theoretically 43.8 mg, 12.6%). LC-MS m / z 417 (M + 1).
Example 60

(Z) -5-((2- (4- (4-Methylpiperazin-1-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1-methyl-4- (piperidin-4-yl) piperazine (12.4 mg, theoretical 40.9 mg, 30.4%). LC-MS m / z 389 (M + 1).
Example 61

(Z) -5-((2- (4- (Dimethylamino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and N, N- Prepared using dimethylpiperidin-4-amine (5 mg, theoretical 35.1 mg, 14.3%). LC-MS m / z 334 (M + 1).
Example 62

(Z) -1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidine-4-carbonitrile was replaced by a general substitution procedure and piperidine-4-carbohydrate. Prepared using nitrile (7.5 mg, theoretical 33.2 mg, 22.6%). LC-MS m / z 316 (M + 1).
Example 63

(Z) -5-((2-((2-hydroxy-2-phenylethyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 2 Prepared with-(methylamino) -1-phenylethanol (10.8 mg, theoretical 37.5 mg, 28.8%). LC-MS m / z 357 (M + 1).
Example 64

General Replacement Procedure 3: In a 2-drum round bottom vial, (Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, DMSO (2 mL, 0. 0). 08M), diisopropylethylamine (34 μL, 0.193 mmol, 1.1 eq) and the appropriate amine (0.175 mmol, 1.0 eq). The reaction mixture was heated to 100 ° C. and shaken for 24 hours. The solvent was removed under reduced pressure (GenevacHT-4). The crude was then loaded with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS triggered fraction collection) with acetonitrile / water gradient and trifluoroacetic acid as modifier. The pure fractions were then concentrated under reduced pressure (GenevacHT-4).
Example 65

(Z) -5-((2- (4- (Aminomethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl ( Prepared using piperidin-4-ylmethyl) carbamate (49 mg, theoretical 55.9 mg, 88%). LC-MS m / z 320 (M + 1).
Example 66

(Z) -5-((2- (Methyl (piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared by the general substitution procedure and tert-butyl 3- ( Prepared with (methylamino) piperidine-1-carboxylate (2.3 mg, theoretically 55.9 mg, 4.1%). LC-MS m / z 320 (M + 1).
Example 67

(Z) -5-((2- (3-Methylpiperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by the general substitution procedure and tert-butyl 2-methylpiperazine Prepared using -1-carboxylate (1.5 mg, theoretically 53.4 mg, 2.8%). LC-MS m / z 306 (M + 1).
Example 68

(Z) -5-((2- (piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and tert-butyl piperazine-1-carboxylate (17.7 mg, theoretical 51 mg, 34.7%). LC-MS m / z 292 (M + 1).
Example 69

(Z) -5-((2- (1,4-diazepan-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and tert-butyl 1, Prepared using 4-diazepan-1-carboxylate (15.2 mg, theoretically 53.4 mg, 28.4%). LC-MS m / z 306 (M + 1).
Example 70

(Z) -5-((2- (3-Aminopyrrolidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted to the general substitution procedure and tert-butylpyrrolidine-3- Prepared using ilcarbamate (16.5 mg, 51 mg theoretical, 32.4%). LC-MS m / z 292 (M + 1).
Example 71

(Z) -5-((2- (3-Aminopiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and tertbutylpiperidin-3-yl Prepared with carbamate (16.9 mg, theoretical 29.8 mg, 53.4%). LC-MS m / z 306 (M + 1).
Example 72
Synthesis of (Z) -5-((6- (2-methoxyethoxy) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione

A 25 mL round bottom flask was charged with 2-methoxyethanol (57 μL, 1 eq) and THF (2.5 mL). 60% NaH in oil (21 mg, 1.1 eq) was added at 0 ° C. under argon. The reaction mixture was stirred at −5 ° C. for 5 minutes and at room temperature for 1 hour 15 minutes. Methyl 2,6-dichloropyrimidine-4-carboxylate (150 mg, 1 eq) dissolved in THF (1 mL) was added at −78 ° C. over 5 min. The reaction mixture was warmed from −78 ° C. to 0 ° C. and stirred for 4 hours. LC-MS after 3 hours (15 ° C.) showed two peaks (2: 1 ratio) with the desired mass at 1.57 minutes and 1.67 minutes (M + 1 = 247 & 249). The reaction mixture was quenched at 0 ° C. with 1,0% NH ₄ Cl (5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give methyl 2-chloro-6- (2-methoxyethoxy) pyrimidine-4-carboxylate and methyl 6-chloro-2- (2- 161 mg of a crude mixture of methoxyethoxy) pyrimidine-4-carboxylate was obtained. This was partially separated on silica gel (10 g, hexane / EtOAc 9: 1 to 7: 3) by flash chromatography.
F1: 47 mg pure desired 6-alkoxy isomer (26%, theoretical 179 mg)
F2: 19.3 mg mixture of isomers (11%)
F3: 28.8 mg pure undesired 2-alkoxy isomer (16%)

Round bottom flask 25 mL, was charged with methyl 2-chloro-6- (2-methoxyethoxy) pyrimidine-4-carboxylate [SAD105-047F1] (45mg, 1 eq) and _CH 2 _Cl 2 (1mL). 1MDIBIAL-H (0.2 mL, 1.1 eq) was added over 2 min at −78 ° C. under argon. The reaction mixture was stirred at −78 ° C. for 3 hours, but LC-MS still showed much starting material. Additional 1MDIBIAL-H (0.27 mL, 1.4 eq) was added over 2 min at −78 ° C. under argon and after 0.5 h, LC-MS showed 1.20 min (M + 1 = 217, M + 1 + MeOH = 249). The starting material was gone except for almost one peak. The reaction mixture was quenched with MeOH (0.5 mL) followed by 10% NH ₄ Cl (1 mL). The reaction mixture was warmed to room temperature and then the solvent was concentrated under reduced pressure. The residue was diluted with 10% NH ₄ Cl (4 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 41.9 mg of crude 2-chloro-6- (2-methoxyethoxy) pyrimidine-4-carbaldehyde as a yellow oil. Obtained and used in the next step without further purification (HNMRδ: 9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3 .7-3.8 (m, 2H); 3.44 (s, 3H).

Crude 2-chloro-6- (2-methoxyethoxy) pyrimidine-4-carbaldehyde (sad105-052, 41.9 mg) was dissolved in ethanol (1.5 mL) and thiazolidine-dione (21.3 mg, 0 .18 mmol) and 1- (p-tolyl) piperazine (39.3 mg, 0.18 mmol). The reaction mixture was shaken at 80 ° C. for 15.5 hours. LC-MS showed a peak with the desired mass at 2.18 min (M + 1 = 456). The solvent was concentrated under reduced pressure and the residue was dissolved in EtOAc (20 mL) and washed with saturated NaHCO ₃ (10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 85.7 mg of a brown oil. Flash chromatography _(SiO 2, 10 g, hexane / EtOAc 9: 1 to 6: 4 to 1: 1) to give the pure 11.5mg (Z) -5 - (( 6- (2- methoxyethoxy) - 2- (4- (p-Tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was obtained as a yellow solid (13.9% theoretical over 2 steps) 83 mg).
Example 73
Synthesis of (Z) -5-((6-methoxy-2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione

In a 40 mL round bottom vial, methanol (120 μL of 200 μL MeOH in 1 mL of acetonitrile, 1 equivalent), K ₂ CO ₃ (67 mg, 1 equivalent), methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 1 equivalent). Eq) and acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 2.5 hours, but LC-MS showed only starting material. The reaction mixture was then shaken at 85 ° C. for 1 hour. LC-MS showed the formation of a small amount of the desired product (1.51 min and M + 1 = 203). Methanol (0.200 mL, 10 eq) was added and the reaction mixture was shaken at 85 ° C. for 15 hours. LC-MS showed approximately one peak of UV and MS at 1.53 minutes, and a trace of bis-methoxypyrimidine. The solid precipitate was filtered and the filtrate evaporated to give 89 mg of crude desired product (91% crude yield, theoretical 98 mg). HNMR showed an 11: 1 mixture of the desired product and bis-methoxypyrimidine byproduct (M + 1 = 199). The material was used in the next step without further purification.

A 25 mL round bottom flask was charged with methyl 2-chloro-6-methoxypyrimidine-4-carboxylate [sad 105-055 crude] (74 mg, 1 eq) under argon. 1M DIBIAL-H in dichloromethane (0.73 mL, 2 eq) was added over 5 minutes and the reaction mixture was stirred at −78 ° C. for 45 minutes. After 0.5 hours, LC-MS showed that the reaction was complete. The reaction was quenched at −78 ° C. with methanol (0.5 mL) and then 10% NH ₄ Cl (2 mL). The solvent was concentrated under reduced pressure and the residue was diluted with 10% NH ₄ Cl (3 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product 2-chloro-6-methoxypyrimidine-4-carbaldehyde as an orange oil (63 mg, theoretically 76 mg, 121%). LC-MS m / z: 205.0: (M + 1 + MeOH, hemiacetal with methanol). Some overreduced alcohol was also observed in the crude material (2.17 min, M + 1 = 175). The crude aldehyde was used directly in the next step without further purification.

Crude 2-chloro-6-methoxypyrimidine-4-carbaldehyde was dissolved in ethanol (2 mL) and thiazolidine-dione (42.8 mg, 0.37 mmol, 1 eq) and 1- (p-tolyl) piperazine ( 70.8 mg, 0.40 mmol, 1.1 equiv). The mixture was shaken at 80 ° C. for 45 hours and 90 ° C. for 15 hours resulting in precipitation. LC-MS of the solution showed some product at (M + 1 = 412) and some intermediate at (M + 1 = 430). The desired product is crashed out of solution and the LC-MS of the solution does not reflect well the conversion of the reaction. The yellow solid was filtered through a glass wool pad using a capillary pipette and the solid was rinsed with EtOH (4 × 0.5 mL). The ethanol filtrate contained some desired product. The solid was redissolved in CH ₂ Cl ₂ and the insoluble solid was filtered. The filtrate was concentrated under reduced pressure and 20 mg of the desired product (Z) -5-((6-methoxy-2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) Thiazolidine-2,4-dione (purity 97.3%) was obtained. The insoluble solid was partitioned between saturated NaHCO ₃ (3 mL) and CH ₂ Cl ₂ (2 × 5 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give an additional 13.4 mg of the desired product (33.4 mg total, 150 mg theoretical, 22%). LC-MS m / z: 412 (M + 1).
Example 74
Synthesis of (Z) -5-((2- (4- (p-tolyl) piperazin-1-yl) pyridin-4-yl) methylene) thiazolidine-2,4-dione

A 40 mL round bottom vial was charged with methyl 2-chloroisonicotinate (200 mg, 1.17 mmol, 1 eq) and 1- (p-tolyl) piperazine (205 mg, 1.17 mmol, 1 eq). Toluene (3 mL) and DMSO (3 mL) were added followed by potassium carbonate (403 mg, 2.9 mmol, 2.5 eq). The mixture was shaken at 100 ° C. for 18 hours. LC-MS after 18:00 showed a peak with the desired mass (M + 1 = 312) at 1.68 minutes, and the chloropyridine starting material (M + 1 = 172) co-eluted. The reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The crude mixture was purified on silica gel (10 g, hexane / EtOAc 9: 1 to 1: 1) to give the desired product as white crystals (27 mg, theoretical 67 mg, 40%).

A 25 mL round bottom flask was charged with methyl 2- (4- (p-tolyl) piperazin-1-yl) isonicotinate (27 mg, 0.087 mmol, 1 eq) and CH ₂ Cl ₂ (1 mL). 1M DIBAL-H in CH ₂ Cl ₂ (130 μL, 0.13 mmol, 1.5 eq) was added over 2 min at −78 ° C. under argon. The reaction mixture was quenched at −78 ° C. with MeOH (0.5 mL). LC-MS of the crude mixture showed a 1: 1 mixture of alcohol (1.21 min, M + 1 = 284) and aldehyde as hemiacetal with methanol (1.38 min, M + 1 + MeOH = 314.3). Indicated. The crude aldehyde was used directly in the next step without further purification.

Crude 2- (4- (p-tolyl) piperazin-1-yl) isonicotinaldehyde [sad105-080] was dissolved in ethanol (1 mL) and thiazolidine-dione (10.2 mg, 0.087 mmol) and 1 -To a 10 mL vial containing (p-tolyl) piperazine (5.9 mg, 0.087 mmol). The reaction mixture was shaken at 90 ° C. for 19.5 hours. LC-MS showed a new peak with the desired mass (M + 1 = 381) at 1.78 minutes. The reaction was concentrated under reduced pressure, the residue was purified by flash chromatography _(SiO 2, 10 g, hexane / EtOAc 9: 1 to 4: 6) to afford, in 10.1mg (Z) -5 - (( 2- (4 -(P-Tolyl) piperazin-1-yl) pyridin-4-yl) methylene) thiazolidine-2,4-dione was obtained as a yellow solid (30% over 2 steps, theoretical 33.1 mg). The yellow solid was dissolved in hot EtOH (0.5 mL). Upon cooling, a yellow solid precipitated and was filtered through a pad of glass wool and washed with 0.25 mL of ethanol. The solid was redissolved in CH ₂ Cl ₂ and concentrated under reduced pressure to give 1.7 mg of the title material. LC-MS m / z: (M + 1 = 381).
Example 75
Synthesis of (Z) -5-((6- (4- (p-tolyl) piperazin-1-yl) pyridin-2-yl) methylene) thiazolidine-2,4-dione

A 40 mL round bottom vial was charged with thiazolidine-2,4-dione (300 mg, 2.56 mmol, 1 eq) and 6-bromopicolinaldehyde (477 mg, 2.56 mmol, 1 eq). Toluene (5 mL, 0.5 M), glacial acetic acid (22 μL, 0.38 mmol, 0.15 equiv) and piperidine (25 μL, 0.25 mmol, 0.1 equiv) were added and the vial was purged with argon. The mixture was shaken at 125 ° C. for 16 hours. The resulting solid was collected by filtration and then washed with acetone (3 × 5 mL). The solid was dried under reduced pressure to give (Z) -5-((6-bromopyridin-2-yl) methylene) thiazolidine-2,4-dione (439 mg, 731 mg on the path, 60%). LC-MS m / z: 286 (M + 1).

In an 8 mL round bottom vial, 1- (p-tolyl) piperazine (56 mg, 0.318 mmol, 1 eq), DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 eq), (Z) −5-((6-Bromopyridin-2-yl) methylene) thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 eq) was charged and the vial purged with argon. The mixture was shaken at 110 ° C. for 48 hours. The reaction mixture was then partitioned between CH ₂ Cl ₂ (10 mL) and saturated NaCl (20 mL). The aqueous layer was extracted back with CH ₂ Cl ₂ (2 × 15 mL) and the combined organic layers were dried over xxx and concentrated under reduced pressure to give an orange residue. The orange residue was triturated with ether (3 × 15 mL) and (Z) -5-((6- (4- (p-tolyl) piperazin-1-yl) pyridin-2-yl) methylene) thiazolidine- 2,4-dione was obtained as an orange solid (65 mg, theoretical 122 mg, 53%). LC-MS m / z: 382 (M + 1).
Example 76

(Z) -5-((6- (methyl (phenethyl) amino) pyridin-2-yl) methylene) thiazolidine-2,4-dione: In an 8 mL round bottom vial, N-methyl-2-phenylethanamine ( 43 mg, 0.318 mmol, 1 eq), DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 eq), (Z) -5-((6-bromopyridin-2-yl) methylene) Thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 eq) was charged and the vial was purged with argon. The mixture was shaken at 110 ° C. for 48 hours. The reaction mixture was then partitioned between CH ₂ Cl ₂ (10 mL) and saturated NaCl (20 mL). The aqueous layer was extracted back with CH ₂ Cl ₂ (2 × 15 mL) and the combined organic layers were dried over xxx and concentrated under reduced pressure to give an orange residue. The orange residue is triturated with ether (3 × 15 mL) and (Z) -5-((6- (methyl (phenethyl) amino) pyridin-2-yl) methylene) thiazolidine-2,4-dione is converted to orange Obtained as a colored film (2.6 mg, theoretically 175 mg, 5%). LC-MS m / z: 340 (M + 1).
Example 77
General procedure for the preparation of amino analogues 1

  Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mL THF was treated with DIPEA (185 μL, 1.06 mmol) and then the reaction was cooled to 0 ° C. A solution of the appropriate amine (1 eq, 0.966 mmol) in 2 mL of THF was then slowly added to the reaction mixture. The reaction mixture was shaken for 2 hours and then concentrated under reduced pressure. A light yellow crude product was obtained. This was used without further purification.

  The light yellow crude product (1 eq) was treated with DCM (2 mL). The reaction mixture was then cooled to −70 ° C., treated dropwise with 1M DIBALH (180 μL, 1.1 eq) and stirred for 2 hours. Further, 100 μL of DIBALH was added dropwise and further stirred for 3 hours. MeOH (1 mL) was then added to quench the reaction. The reaction mixture was then warmed to room temperature and partitioned between water (5 mL) and DCM (5 mL). The DCM layer was collected and concentrated under reduced pressure. The desired aldehyde was obtained by flash chromatography using 50% -80% EtOAc / hexanes.

The aldehyde was treated with thiazolidine-2,4-dione (1 eq) and 1- (p-tolyl) piperazine (1.1 eq) in 2 mL EtOH. The reaction mixture was then heated to 85 ° C. for 16 hours and then further heated to 95 ° C. for 24 hours. The reaction mixture was then concentrated and purified by Biotage chromatography using 1: 1 hexane / EtOAc to give the final amino analog.
Example 78

(Z) -5-((6- (Methyl (phenethyl) amino) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using general procedure 1 for the preparation of amino analogs and N-methyl-2-phenylethanamine (4.2 mg, theoretical 90 mg, 5% over 3 steps). LC-MS m / z: 515 (M + 1).
Example 79

(Z) -5-((6- (benzyl (methyl) amino) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using general procedure 1 for the preparation of amino analogs and N-methylbenzylamine (5.1 mg, theoretically 85 mg, 6% over 3 steps). LC-MS m / z: 501 (M + 1).
Example 80

(Z) -5-((6-((2-methoxyethyl) (methyl) amino) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2 , 4-dione was prepared using the general substitution procedure and N-methyl-2-phenylethanamine (34 mg, 142 mg theoretically 23.9% over 3 steps). LC-MS m / z 501: (M + 1).
Example 81
General procedure for the preparation of amino analogues 2

  Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mL of THF was treated with DIPEA (185 μL, 1.06 mmol) and then cooled to 0 ° C. A solution of the appropriate amine (1 eq, 0.966 mmol) in 2 mL of THF was then added slowly. The reaction mixture was shaken for 2 hours and concentrated under reduced pressure to give a light yellow crude product. This was used without further purification.

  The crude material was treated with 2 mL EtOH, DIPEA (1.1 eq) and 1- (p-tolyl) piperazine (1 eq). The reaction mixture was then heated to 90 ° C. for 2 days. LCMS showed the desired product with an EtO version of the ester. The reaction mixture was then concentrated under reduced pressure and purified using Biotage with 10-100% EtOAc / hexanes to give the desired diamino ester intermediate.

The diamino ester intermediate was treated with DCM (2 mL) and cooled to −10 ° C. DIBALH (3 eq) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 1 hour. Methanol (1 mL) was added to quench the reaction and then stirred for 30 minutes. The reaction mixture was then partitioned between DCM (10 mL) and H ₂ O (10 mL). The aqueous layer was extracted back with DCM (2 × 10 mL) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified on silica gel using 5-10% MeOH / DCM to give the desired alcohol. The alcohol (1 eq) was treated with 2 mL of DCM, the reaction mixture was cooled to 0 ° C. and treated with 1.4 mL of 15% desmartin reagent in DCM. The reaction mixture was stirred for 1 hour, treated with an additional portion of Dess-Martin reagent (1.1 eq) at 0 ° C., warmed to room temperature and stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure and the crude residue was purified by flash chromatography using 5-10% MeOH / DCM to give the desired aldehyde.

The aldehyde was treated with thiazolidine-2,4-dione (1 eq), piperidine (0.8 eq), and 2 mL EtOH. The reaction mixture was then heated to 85 ° C. for 16 hours and then concentrated under reduced pressure, then the residue was triturated with DCM (2 mL), MeOH (2 mL) and EtOAc (2 mL) to give the final amino analog. It was.
Example 82

(Z) -5-((6- (methyl (2- (pyridin-2-yl) ethyl) amino) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene ) Thiazolidine-2,4-dione was prepared using the general substitution procedure and N-methyl-2- (pyridin-2-yl) ethanamine. (12.7 mg, theoretically 160 mg, 1.7%, 5 steps). LC-MS m / z: 516 (M + 1).
Example 83

(Z) -5-((6-((2-methoxyethyl) (methyl) amino) -2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2 , 4-dione was prepared using the general substitution procedure and 2-methoxy-N-methylethanamine. (34 mg, theoretically 680 mg, 5%, 5 steps). LC-MS m / z: 469 (M + 1).
Example 84



(Z) -2- (2,4-Dioxo-5-((2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidin-3-yl) acetamide

10 mg of (Z) -5-((2- (4- (p-tolyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, 4 mg of 2-bromoacetamide, carbonic acid 4 mg of potassium and 0.5 mL of DMF were added. The reaction mixture is heated to 55 ° C. for 4 hours, concentrated under reduced pressure, purified using reverse phase HPLC (MS-triggered fraction collection) and acetonitrile / water gradient using trifluoroacetic acid as a modifier. did. The pure fraction was then concentrated under reduced pressure (GenevacHT-4) and (Z) -2- (2,4-dioxo-5-((2- (4- (p-tolyl) piperazin-1-yl). ) Pyrimidin-4-yl) methylene) thiazolidin-3-yl) acetamide was obtained (4 mg, theoretical 11.5 mg, 35%). LC-MS m / z: 439 (M + 1).
Example 85

General Replacement Procedure: A 2-drum round bottom vial was prepared according to the general procedure (Z) -5-((2- (methylsulfonyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 eq), and the appropriate amine (0.0877 mmol, 1.0 eq) were charged. The reaction mixture was heated to 110 ° C. and shaken for 24 hours. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS triggered fraction collection) with acetonitrile / water gradient and trifluoroacetic acid as modifier. The pure fraction was then concentrated under reduced pressure (Genvac HT-4).
Example 86

(Z) -5-((2- (4- (3- (pyridin-4-yl) -1,2,4-oxadiazol-5-yl) piperidin-1-yl) pyrimidin-4-yl) Methylene) thiazolidine-2,4-dione prepared using the general substitution procedure and 5- (piperidin-4-yl) -3- (pyridin-4-yl) -1,2,4-oxadiazole did. LC-MS m / z 436.4 (M + 1).
Example 87

(Z) -5-((2- (Butyl (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and N-methylbutan-1-amine (30 7 mg theoretically 12.5 mg, 40.7%). LC-MS m / z 293.3 (M + 1).
Example 88

(Z) -5-((2- (Isoquinolin-2 (1H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted to the general substitution procedure 1,2,3,4-tetrahydro. Prepared with isoquinoline (2 mg, theoretically 35 mg, 5.7%). LC-MS m / z 337.1 (M + 1).
Example 89

(Z) -5-((2- (Methyl (pyridin-4-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and N-methylpyridine- Prepared with 4-amine (11.7 mg, theoretical 32.9 mg, 35.5%). LC-MS m / z 314.3 (M + 1).
Example 90

(Z) -5-((2- (7-amino-3,4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution. Prepared using the procedure and 1,2,3,4-tetrahydroisoquinolin-7-amine (12.8 mg, theoretical 37.2 mg, 34.4%). LC-MS m / z 354.3 (M + 1).
Example 91

(Z) -5-((2- (3,4-dihydro-1H-pyrido [4,3-b] indol-2 (5H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4- The dione was prepared using the general substitution procedure and 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (4.2 mg, theoretical 39.7 mg, 10.6%) . LC-MS m / z 378.4 (M + 1).
Example 92

(Z) -5-((2-(((1-methylpiperidin-4-yl) methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1 Prepared with-(methylpiperidin-4-yl) methanamine (7.4 mg, theoretical 29.2 mg, 25.3%). LC-MS m / z 334.1 (M + 1).
Example 93

(Z) -5-((2- (4- (2- (dimethylamino) ethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And N, N, N-dimethylanilin-2- (piperidin-4-yl) ethanamine (20.6 mg, theoretically 38.0 mg, 54.2%). LC-MS m / z 362.2 (M + 1).
Example 94

(Z) -5-((2- (4- (1H-Indol-3-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and Prepared using 3- (piperidin-4-yl) -1H-indole. (7.2 mg, theoretically 42.6 mg, 16.8%). LC-MS m / z 406.1 (M + 1).
Example 95

(Z) -5-((2- (4- (1H-Indol-3-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is a general substitution procedure and Prepared using N, N-dimethyl-1- (piperidin-4-yl) methanamine (23.1 mg, theoretical 36.5 mg, 63.2%). LC-MS m / z 348.1 (M + 1).
Example 96

(Z) -5-((2- (3-Fluoropiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 3-fluoropiperidine Prepared (7.7 mg, theoretical 32.4 mg, 23.7%). LC-MS m / z 309.1 (M + 1).
Example 97

(Z) -5-((2- (4-Methylpiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 4-methylpiperidine Prepared (16.4 mg, theoretical 32 mg, 51.2%). LC-MS m / z 305.1 (M + 1).
Example 98

(Z) -5-((2- (4- (Hydroxymethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and piperidin-4-yl. Prepared using methanol (17.8 mg, theoretical 33.7 mg, 52.8%). LC-MS m / z 321.1 (M + 1).
Example 99

(Z) -5-((2- (3,5-Dimethylpiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 3,5-dimethylpiperidine (1.3 mg, theoretical 33.5 mg, 3.9%). LC-MS m / z 319.1 (M + 1).
Example 100

(Z) -5-((2- (8-methyl-2,8-diazaspiro [5.5] undecano-2-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a simple substitution procedure and 2-methyl-2,8-diazaspiro [5.5] undecane (23.5 mg, theoretical 39.3 mg, 59.8%). LC-MS m / z 374.2 (M + 1).
Example 101

(Z) -5-((2- (3- (piperidin-1-ylmethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and 1- ( Prepared using piperidin-3-ylmethyl) piperidine (21.8 mg, theoretical 40.7 mg, 53.5%). LC-MS m / z 388.5 (M + 1).
Example 102

(Z) -5-((2- (2- (2-Hydroxyethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and 2- ( Prepared using piperidin-2-yl) ethanol (10.1 mg, theoretical 35.2 mg, 28.7%). LC-MS m / z 335.1 (M + 1).
Example 103

(Z) -5-((2- (3- (1H-pyrazol-1-yl) azetidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and Prepared using 1- (azetidin-3-yl) -1H-pyrazole (24.3 mg, theoretical 34.5 mg, 70.4%). LC-MS m / z 329.1 (M + 1).
Example 104

(Z) -5-((2- (3-((dimethylamino group) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and N , N-dimethyl-1- (piperidin-3-yl) methanamine (23.4 mg, theoretical 36.5 mg, 64.1%). LC-MS m / z 348.4 (M + 1).
Example 105

(Z) -5-((2- (8-benzyl-2,8-diazaspiro [5.5] undecano-2-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is Prepared using the substitution procedure and 2-benzyl-2,8-diazaspiro [5.5] undecane (15.3 mg, 47.3 mg theoretical, 32.4%). LC-MS m / z 450.5 (M + 1).
Example 106

(Z) -5-((2- (4- (2-hydroxyethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and 2- ( Prepared using piperidin-4-yl) ethanol (18.1 mg, theoretical 47.2 mg, 38.4%). LC-MS m / z 335.1 (M + 1).
Example 107

(Z) -5-((2- (4- (2- (piperidin-1-yl) ethyl) piperazin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using the displacement procedure and 1- (2- (piperidin-1-yl) ethyl) piperazine (36.6 mg, 66.3 mg theoretical, 55.2%). LC-MS m / z 403.2 (M + 1).
Example 108

(Z) -5-((2- (2-Methylpiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and 2-methylpiperidine. (2.5 mg, theoretically 32 mg, 7.8%). LC-MS m / z 305.1 (M + 1).
Example 109

(Z) -5-((2- (4-Hydroxypiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, a general substitution procedure, and piperidin-4-ol (19.9 mg, theoretical 33.7 mg, 52.8%). LC-MS m / z 321.1 (M + 1).
Example 110

(Z) -5-((2- (4-Fluoropiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 4-fluoropiperidine Prepared (12 mg, theoretical 32.4 mg, 37%). LC-MS m / z 309.1 (M + 1).
Example 111

(Z) -5-((2- (3- (Pyrrolidin-1-ylmethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione and the general substitution procedure and 3- ( Prepared using pyrrolidin-1-ylmethyl) piperidine (4.3 mg, theoretical 39.3 mg, 11%). LC-MS m / z 374.5 (M + 1).
Example 112

(Z) -5-((2-((2- (dimethylamino group) ethyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and N1, Prepared using N1, N2-trimethylethane-1,2-diamine (5.6 mg, 32.3 mg theoretical, 17.3%). LC-MS m / z 308.4 (M + 1).
Example 113

(S, Z) -5-((2-((1-Hydroxybutan-2-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and amine (6.6 mg, theoretical 30.9 mg, 21.3%). LC-MS m / z 295.1 (M + 1).
Example 114

(Z) -5-((2- (3- (Hydroxymethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced with the general substitution procedure and (S) -2. Prepared using aminobutan-1-ol (13.5 mg, theoretical 33.7 mg, 40.1%). LC-MS m / z 321.1 (M + 1).
Example 115

(Z) -5-((2- (4,4-Bi (hydroxymethyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and piperidine-4. , 4-diyldimethanol (10 mg, theoretical 36.8 mg, 27.1%). LC-MS m / z 351.1 (M + 1).
Example 116

(Z) -5-((2- (3-Hydroxypiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and piperidin-3-ol. (6.3 mg, theoretical 32.2 mg, 19.6%). LC-MS m / z 307.1 (M + 1).
Example 117

(Z) -5-((2- (3-Methylpiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione using the general substitution procedure and 3-methylpiperidine Prepared (10.3 mg, theoretical 32 mg, 32.2%). LC-MS m / z 305.1 (M + 1).
Example 118

(S, Z) -5-((2- (Methyl (1-methylpiperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and (S ) -N, 1-dimethylpiperidin-3-amine (11.2 mg, theoretically 58.4 mg, 19.2%). LC-MS m / z 334.1 (M + 1).
Example 119

(Z) -5-((2- (cyclohexyl (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and N-methylcyclohexaneamine. (3.4 mg, theoretical 33.5 mg, 10.2%). LC-MS m / z 319.1 (M + 1).
Example 120

(Z) -5-((2- (5-Amino-3,4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1,2,3,4-tetrahydroisoquinolin-5-amine (8.2 mg, theoretical 37.2 mg, 22%). LC-MS m / z 354.1 (M + 1).
Example 121

(Z) -5-((2- (cyclohexylamino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared using the general substitution procedure and cyclohexaneamine (3.6 mg, theory Top 32 mg, 11.2%). LC-MS m / z 305.1 (M + 1).
Example 122

(Z) -1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidine-4-carboxamide was used as a general substitution procedure and piperidine-4-carboxamide (16.7 mg, theoretically 35.1 mg, 47.6%). LC-MS m / z 334.1 (M + 1).
Example 123

(Z) -5-((2-((4- (m-Tolylamino) -5,6,7,8-tetrahydroquinazolin-6-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4 -Diones were prepared using the general substitution procedure and N4- (m-tolyl) -5,6,7,8-tetrahydroquinazoline-4,6-diamine (5.2 mg, theoretically 48.3 mg, 10.8%). LC-MS m / z 460.5 (M + 1).
Example 124

(Z) -5-((2- (4-Oxo-1-phenyl-1,3,8-triazaspiro [4.5] decan-8-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -Dione was prepared using the general substitution procedure and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (12.4 mg, theoretical 38.2 mg, 32.4 %). LC-MS m / z 437.1 (M + 1).
Example 125

(Z) -5-((2- (3- (3-Ethyl-1,2,4-oxadiazol-5-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general substitution procedure and 3-ethyl-5- (piperidin-3-yl) -1,2,4-oxadiazole (11.9 mg, theoretical 33.9 mg, 35.1%). LC-MS m / z 387.1 (M + 1).
Example 126

(Z) -5-((2- (4- (4,6-diamino-1,3,5-triazin-2-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general substitution procedure and 6- (piperidin-4-yl) -1,3,5-triazine-2,4-diamine (13.0 mg, theoretically 35.0 mg, 37.1%). LC-MS m / z 400.1 (M + 1).
Example 127

(Z) -5-((2- (3-((1H-benzo [d] imidazol-2-yl) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Was prepared using the general substitution procedure and 2- (piperidin-3-ylmethyl) -1H-benzo [d] imidazole (29.3 mg, theoretical 44.2 mg, 66.3%). LC-MS m / z 421.5 (M + 1).
Example 128

(Z) -5-((2- (3- (4-Methyl-1H-benzo [d] imidazol-2-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4- The dione was prepared using the general substitution procedure and 4-methyl-2- (piperidin-3-yl) -1H-benzo [d] imidazole (18.9 mg, theoretical 44.2 mg, 42.7% ). LC-MS m / z 421.5 (M + 1).
Example 129

(Z) -5-((2- (4- (6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] azepin-3-yl) piperidine-1 -Yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted to the general substitution procedure and 3- (piperidin-4-yl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] azepine (16.2 mg, theoretically 44.7 mg, 36.2%). LC-MS m / z 426.5 (M + 1).
Example 130

(Z) -5-((2-(((1-ethyl-1H-pyrazol-5-yl) methyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 1- (1-ethyl-1H-pyrazol-5-yl) -N-methylmethanamine (7.2 mg, theoretical 36.2 mg, 20%). LC-MS m / z 345.1 (M + 1).
Example 131

(Z) -5-((2- (3- (6-hydroxy-2-methylpyrimidin-4-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 2-methyl-6- (piperidin-3-yl) pyrimidin-4-ol (16.8 mg, 41.9 mg theoretical, 40.1%). LC-MS m / z 399.1 (M + 1).
Example 132

(Z) -5-((2- (3-([1,2,4] triazolo [4,3-a] pyridin-1-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine -2,4-dione was prepared using the general substitution procedure and 3- (piperidin-3-yl)-[1,2,4] triazolo [4,3-a] pyridine (11 mg, theoretically 42.8 mg, 25.7%). LC-MS m / z 408.5 (M + 1).
Example 133

(Z) -5-((2- (4-amino-3,4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1,2,3,4-tetrahydroisoquinolin-4-amine (1.4 mg, 37.2 mg theoretical, 3.8%). LC-MS m / z 354.1 (M + 1).
Example 134

(Z) -5-((2- (4- (1H-tetrazol-5-yl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure; And 4- (1H-tetrazol-5-yl) piperidine (4 mg, theoretical 37.7 mg, 10.6%). LC-MS m / z 359.1 (M + 1).
Example 135

(Z) -5-((2- (Methyl (thiophen-3-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and N-methyl-1- Prepared using (thiophen-3-yl) methanamine (35 mg theoretically 7.5 mg, 21.5%) (7.5 mg, theoretically 35 mg, 21.5%). LC-MS m / z 333.0 (M + 1).
Example 136

(Z) -5-((2- (2,4-Dioxo-1,3,8-triazaspiro [4.5] decan-8-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Was prepared using the general substitution procedure and 1,3,8-triazaspiro [4.5] decane-2,4-dione (15.2 mg, theoretical 39.4 mg, 38.6%). LC-MS m / z 375.1 (M + 1).
Example 137

(Z) -5-((2-(((1H-benzo [d] imidazol-2-yl) methyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general substitution procedure and 1- (1H-benzo [d] imidazol-2-yl) -N-methylmethanamine (6.6 mg, 38.5 mg theoretical, 17%). LC-MS m / z 367.1 (M + 1).
Example 138

(Z) -5-((2-((3-Aminobenzyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and 3-((methylamino ) Methyl) aniline (19.7 mg, theoretical 35.9 mg, 54.9%). LC-MS m / z 342.1 (M + 1).
Example 139

(Z) -5-((2-((2- (1H-Indol-3-yl) ethyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution. Prepared using the procedure and 2- (1H-indol-3-yl) -N-methylethanamine (8.3 mg, 39.9 mg theoretical, 20.8%). LC-MS m / z 380.4 (M + 1).
Example 140

(Z) -5-((2-((1,2,3,4-tetrahydroquinolin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure. And 1,2,3,4-tetrahydroquinolin-3-amine (5 mg, 37.2 mg theoretical, 13.5%). LC-MS m / z 354.1 (M + 1).
Example 141
Substitution / deprotection of mono-Boc diamine

Example 142

(R, Z) -5-((2- (Methyl (piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and (R) -tert. Prepared using -butyl 3- (methylamino) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (3.1 mg, theoretical 55.9 mg, 5.5%). LC-MS m / z 320.1 (M + 1).
Example 143

(S, Z) -5-((2- (Methyl (piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and (S) -tert Prepared using -butyl 3- (methylamino) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (3.2 mg, 55.9 mg theoretical, 5.7%). LC-MS m / z 320.1 (M + 1).
Example 144

(S, Z) -5-((2- (piperidin-3-ylamino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and (R) -tert-butyl 3- Prepared using aminopiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (6.9 mg, theoretical 32.1 mg, 21.5%). LC-MS m / z 306.1 (M + 1).
Example 145

(R, Z) -5-((2- (piperidin-3-ylamino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by the general substitution procedure and (S) -tert-butyl 3 -Prepared using aminopiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (3.8 mg, theoretical 32.1 mg, 11.8%). LC-MS m / z 306.1 (M + 1).
Example 146

(Z) -5-((2-((piperidin-2-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl 2- (aminomethyl). ) Prepared with piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (10.7 mg, 45.6 mg theoretical, 23.5%). LC-MS m / z 320.1 (M + 1).
Example 147

(Z) -5-((2-((piperidin-4-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl 4- (aminomethyl ) Prepared with piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (5.3 mg, 33.5 mg theoretical, 15.8%). LC-MS m / z 320.1 (M + 1).
Example 148

(R, Z) -5-((2-((piperidin-3-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by the general substitution procedure and (S) -tertbutyl. Prepared using 3- (aminomethyl) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (7.3 mg, theoretical 33.5 mg, 21.8%). LC-MS m / z 320.1 (M + 1).
Example 149

(Z) -5-((2- (Methyl (piperidin-3-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl 3-(( Prepared using methylamino) methyl) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (21.6 mg, theoretical 35 mg, 61.7%). LC-MS m / z 334.1 (M + 1).
Example 150

(Z) -5-((2- (3-((methylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert- Prepared using butylmethyl (piperidin-3-ylmethyl) carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (17.9 mg, theoretical 35 mg, 51.1%). LC-MS m / z 334.1 (M + 1).
Example 151

(Z) -5-((2- (methyl (piperidin-4-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tertbutyl-4-(( Prepared using methylamino) methyl) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (6.5 mg, theoretical 35 mg, 18.6%). LC-MS m / z 334.1 (M + 1).
Example 152

(S, Z) -5-((2-((piperidin-3-ylmethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and (R) -tert. Prepared with -butyl 3-((methylamino) methyl) piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (11.2 mg, theoretical 33.5 mg, 33.4%). LC-MS m / z 320.1 (M + 1).
Example 153

(Z) -5-((2-((2-aminoethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by the general substitution procedure and tert-butyl (2-aminoethyl) Prepared using carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (10.7 mg, theoretical 27.9 mg, 38.4%). LC-MS m / z 266.1 (M + 1).
Example 154

(Z) -5-((2- (3- (methylamino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butylmethyl ( Prepared using piperidin-3-yl) carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (26.9 mg, 33.5 mg theoretical, 80%). LC-MS m / z 320.1 (M + 1).
Example 155

(Z) -5-((2- (Octahydro-1,5-naphthyridin-1 (2H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert- Prepared using butyloctahydro-1,5-naphthyridine-1 (2H) -carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (7.2 mg, theoretical 36.3 mg, 19.8%). LC-MS m / z 346.1 (M + 1).
Example 156

(Z) -5-((2-((3-aminobenzyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl (3- (aminomethyl ) Phenyl) carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (6.5 mg, 28.7 mg theoretical, 22.7%). LC-MS m / z 328.1 (M + 1).
Example 157

(Z) -5-((2-((5-phenylpiperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and tert-butyl 3- Prepared using amino-5-phenylpiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (5.6 mg, theoretical 33.4 mg, 16.8%). LC-MS m / z 382.1 (M + 1).
Example 158

(Z) -5-((2-((4-Phenylpiperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared by the general substitution procedure and tert-butyl 3- Prepared using amino-4-phenylpiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (5.7 mg, theoretical 33.4 mg, 17.1%). LC-MS m / z 382.1 (M + 1).
Example 159

(Z) -5-((2-((3- (aminomethyl) benzyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared by the general substitution procedure and tert-butyl 3- ( Prepared using aminomethyl) benzylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (16.6 mg, theoretical 35.8 mg, 46.3%). LC-MS m / z 342.1 (M + 1).
Example 160

(Z) -5-((2- (Octahydro-1,5-naphthyridin-1 (2H) -yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to the general substitution procedure and 3- Prepared using ((tert-butoxycarbonyl) amino) -3- (piperidin-4-yl) propanoic acid. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (24.6 mg, theoretical 11.8 mg, 208%). LC-MS m / z 378.4 (M + 1).
Example 161

(S, Z) -5-((2- (3-Aminopiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and (S) -tert. Prepared using butylpiperidin-3-ylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (46.8 mg, theoretical 30.2 mg, 155%). LC-MS m / z 306.1 (M + 1).
Example 162

(R, Z) -5-((2- (3-Aminopiperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was replaced by a general substitution procedure and (R) -tertbutyl. Prepared using piperidin-3-ylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL TFA and shaken for 24 hours. The solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is removed using acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoroacetic acid as modifier. Purified. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) (44.2 mg, 30.2 mg theoretical, 146%). LC-MS m / z 306.1 (M + 1).
Example 163

(Z) -5-((6- (Methyl (piperidin-3-yl) amino) -2- (piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using general procedure 2 for the preparation of the body (Example 81) using tert-butyl 3- (methylamino) piperidine-1-carboxylate and piperidine (11.4 mg, theoretically 54. 0 mg, 21.1%). LC-MS m / z 403.2 (M + 1).
Example 164

(Z) -5-((2- (methyl (piperidin-3-yl) amino) -6- (piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using piperidine and tert-butyl 3- (methylamino) piperidine-1-carboxylate using general procedure 2 for the preparation of the body (Example 81) (10.5 mg, theoretically 26 .3 mg, 41.9%). LC-MS m / z 403.2 (M + 1).

Example 165

(Z) -5-((2,6-di (piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared according to general procedure 2 for the preparation of amino analogues Example 81) was prepared using piperidine (14.0 mg, theoretically 233 mg, 6%). LC-MS m / z 374.2 (M + 1).
Example 166

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is as follows: Prepared.


4-Methyl-2- (methylthio) -6- (trifluoromethyl) pyrimidine

In a 30 mL round bottom vial, 1,1,1-trifluoropentane-2,4-dione (2.00 g, 13.0 mmol, 1 eq), ethanol (15 mL, 0.8 M), thiomethylisourea hemisulfate (1 .807 g, 6.5 mmol, 1 eq) and the reaction mixture was shaken at 80 ° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (25 mL) and saturated NaHCO ₃ (25 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude desired pyrimidine as a slightly orange solid. Biotage: purified using _(SiO 2, 25 g cartridge, hexane / EtOAc 95 5 75:25), the pure desired product 1.66g was obtained (theory 2.70 g, 61.4 %). LC-MS m / z 209 (M + 1).

(Z) -5-((2- (methylthio) -6- (trifluoromethyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione

To a 30 mL round bottom vial was added 4-methyl-2- (methylthio) -6- (trifluoromethyl) pyrimidine (0.500 g, 2.4 mmol, 1 eq), ethanol (5 mL, 0.48 M), selenium dioxide ( 0.293 mg, 2.6 mmol, 1.1 eq.) And the reaction mixture was shaken at 90 ° C. for 40 hours and then at room temperature for 14 days. The crude reaction mixture was then treated with thiazolidine-2,4-dione (0.281 g, 2.4 mmol, 1 equiv), triethylamine (1.0 mL, 7.20 mmol, 3 equiv) and the reaction mixture was 80 ° Shake at C for 16 hours. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified using Biotage (SiO ₂ , 10 g cartridge, CH ₂ Cl ₂ / MeOH 99: 1 to 9: 1) to give 270 mg of partially purified product. This was re-purified using Biotage (SiO ₂ , 10 g cartridge, hexane / EtOAc 90:10 to 0: 1, then CH ₂ Cl ₂ / MeOH 99: 1 to 9: 1) to give 212 mg of yellow solid Obtained. This was not yet completely pure but was used directly in the next step without further purification.

(Z) -5-((2- (methylsulfonyl) -6- (trifluoromethyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione

An 8 mL round bottom vial was charged with pyrimidine sulfide (212 mg, 0.66 mmol, 1 eq) and CH ₂ Cl ₂ (3 mL, 0.22 M), 50 wt% m-CPBA (0.683 g, 1.98 mmol, 3 Equivalent) was added over 1 minute at room temperature. After 3.5 hours, another 3 equivalents of m-CPBA 50 wt% (0.683 g, 1.98 mmol, 3 equivalents) were added and the reaction mixture was stirred at room temperature overnight. The resulting white solid was filtered and washed with CH ₂ Cl ₂ then Et ₂ O to give 67 mg of an off-white solid (theoretical 233 mg, 28.7%). This was used in the next step without further purification. LC-MS m / z 354 (M + 1).

(Z) -tert-butyl ((1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) -6- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) Methyl) carbamate

To an 8 mL round bottom vial was 2-sulfone pyrimidine (67 mg, 0.19 mmol, 1 eq), DMSO (1 mL, 0.19 M), tert-butyl (piperidin-4-ylmethyl) carbamate (40.6 mg, 0.19 mmol). 1 equivalent), DIPEA (66 μL, 0.38 mmol, 2 equiv) was charged and the reaction mixture was stirred at room temperature for 1 hour and then at 50 ° C. for 3 hours. The reaction was purified directly using reverse phase HPLC (500 μL 2 injections, 12 min method, methanol / water gradient with 0.4% TFA) to give the desired product (15.3 mg, theory). Top 92.7 mg, 16.5%).
.

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione

An 8 mL round bottom vial is charged with CF ₃ -pyrimidine (15.3 mg, 0.031 mmol, 1 eq), CH ₂ Cl ₂ (1 mL, 0.03 M), TFA (0.5 mL, 6.5 mmol, 208 eq). And the reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was dried under high vacuum. The residue was washed with ether (2 × 2 mL) and the yellow solid was dried overnight under high vacuum to give (13.4 mg, theoretical 15.8 mg, 85%). LC-MS m / z 388.1 (M + 1).
Example 167

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) -6-methoxypyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared as follows.


Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate

To a 30 mL round bottom vial was added methyl 2,6-dichloropyrimidine-4-carboxylate (0.6 g, 2.9 mmol, 1 eq), methanol (6 mL, 0.97 M), K ₂ CO ₃ (0.401 g, 2.9 mmol, 1 eq) and the reaction mixture was shaken at 65 ° C. for 1.5 hours. The solvent was concentrated under reduced pressure, the residue was partitioned between EtOAc (25 mL) and H ₂ O (25 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude chloropyrimidine (441 mg, theoretical 588 mg, 75%). This was used in the next step without further purification.

Methyl 2- (4-(((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -6-methoxypyrimidine-4-carboxylate

To an 8 mL round bottom vial was added 2-chloropyrimidine (150 mg, 0.74 mmol, 1.5 eq), methanol (1.5 mL, 0.49 M), tert-butyl (piperidin-4-ylmethyl) carbamate (159 mg,. 49 mmol, 1 eq), DIPEA (258 μL, 0.99 mmol, 2 eq) was charged and the reaction mixture was shaken at 65 ° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and saturated NaHCO ₃ (10 mL). The organic layer was dried over Na ₂ SO ₄ and dried under reduced pressure to give the crude product. Purification using Biotage (SiO ₂ , 10 g cartridge, hexane / EtOAc 95: 5 to 40:60) afforded the desired pyrimidine intermediate as a white solid (219 mg, theoretical 281 mg, 78%).

tert-Butyl ((1- (4-formyl-6-methoxypyrimidin-2-yl) piperidin-4-yl) methyl) carbamate

A 50 mL two-necked round bottom flask is charged with the methyl ester intermediate (150 mg, 0.39 mmol, 1 eq), CH ₂ Cl ₂ (2 mL, 0.195 M), then CH ₂ Cl ₂ (0.59 mL, 0 DIBAL-H1M in .59 mmol, 1.5 eq.) Was added over 4 minutes at -78 ° C. The reaction was then stirred at −78 ° C. for 1.5 hours and between −78 ° C. and room temperature for 1.5 hours. LC-MS showed mainly starting material, thus the reaction mixture was re-cooled at -78 ° C. Also DIBIAL-H (0.8 mL, 0.8 mmol, 2 eq) was added. LC-MS showed mainly starting material. The reaction mixture was stored at −20 ° C. for 3 days. The reaction mixture was cooled to −78 ° C. and treated with 1M DIBAL-H in hexane (0.59 mL, 0.59 mmol, 1 eq) for 5 min to produce a white precipitate. After 2.5 hours, an additional equivalent of DiBAL-H (1M in hexane, 0.59 mL) was added over 15 minutes at -78 ° C. The reaction was quenched with methanol (1 mL) at −78 ° C. after 35 minutes. The solvent was concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and saturated NaHCO ₃ (20 mL). The organic layer was dried over Na ₂ SO ₄ and the solvent was concentrated under reduced pressure to give the crude product. This was used in the next step without further purification.

(Z) -tert-butyl ((1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) -6-methoxypyrimidin-2-yl) piperidin-4-yl) methyl) carbamate

In an 8 mL round bottom vial, crude aldehyde (0.2 mmol, estimated), ethanol (2 mL), thiazolidine-2,4-dione (23 mg, 0.2 mmol, 1 eq), triethylamine (56 μL, 0.4 mmol, 2 Eq.), Purged with Ar, and the reaction mixture was shaken at 80 ° C. for 24 h. The crude mixture was purified using Biotage (SiO ₂ , 10 g cartridge, CH ₂ Cl ₂ / MeOH 99: 1 to 94: 6) to give 113 mg of partially purified product. The sample was repurified using reverse phase HPLC (methanol / water 10-90%, 0.4% TFA, 3 equivalent injections) to give pure product as TFA salt (47. 3 mg, theoretically 225 mg, 21%). LC-MS m / z 450 (M + 1).

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) -6-methoxypyrimidin-4-yl) methylene) thiazolidine-2,4-dione

In an 8 mL round bottom vial, MeO-pyrimidine boc protected amine (47.3 mg, 105 μmol, 1 eq), CH ₂ Cl ₂ (1.3 mL, 0.08 M), TFA (0.5 mL, 6.5 mmol, 62 eq) ) And the reaction mixture was stirred at room temperature for 1 hour. The solvent is concentrated under reduced pressure and the residue is redissolved in DMSO (0.9 mL) and purified by reverse phase HPLC (methanol / water with 0.4% TFA, 10-90% method, 2 × 500 μL injection). Purification gave the compound as a TFA salt (43.9 mg, theoretical 48.8 mg, 90%). LC-MS m / z 350.1 (M + 1).
Example 168

(Z) -5-((6- (piperidin-1-yl) pyridin-2-yl) methylene) thiazolidine-2,4-dione was prepared as follows.

  In a 30 mL round bottom vial thiazolidine-2,4-dione (300 mg, 2.56 mmol, 1 eq) toluene (5 mL, 0.5 M), 6-bromopicolinaldehyde (477 mg, 2.56 mmol, 1 eq), glacial acetic acid (22 μL, 0.256 mmol, 0.1 eq), piperidine (25 μL, 0.256 mmol, 0.1 eq) were charged, purged with Ar, and heated at 125 ° C. with shaking. After 16 hours of heating, the yellow reaction solution was pipetted from the solid precipitate. The precipitate was washed with acetone (3 × 5 mL) and dried under high vacuum to give the desired product as a solid (439 mg, theoretical 731 mg, 60%). This was used in the next step without further purification.

In a 2-drum round bottom vial, (Z) -5-((6-bromopyridin-2-yl) methylene) thiazolidine-2,4-dione, DMSO (1 mL, 0.08 M), diisopropylethylamine (34 μL, 0 .2 mmol, 1 eq) and piperidine (21 μL, 0.21 mmol, 1 eq) were charged and the reaction was heated at 110 ° C. with shaking for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residue was purified using reverse phase HPLC (MS triggered fraction collection) with acetonitrile / water gradient and trifluoroacetic acid as modifier. The pure fraction was then concentrated under reduced pressure (Genvac HT-4) and (Z) -5-((6- (piperidin-1-yl) pyridin-2-yl) methylene) thiazolidine-2,4-dione Was obtained (7.9 mg, theoretically 60.9 mg, 12.9%). LC-MS m / z 290.1 (M + 1).
Example 169
Synthetic reductive amination analogues

General Reductive Amination Procedure: In a two-drum round bottom vial, add the crude amine / TFA salt (0.115 mmol), DCE (prepared using the general replacement procedure followed by the general TFA deprotection procedure). 2 mL), DIPEA (6 eq, 0.690 mmol), DMF (1 mL), the aldehyde (1 eq, 0.115 mmol) were charged and the reaction mixture was shaken at room temperature for 1 h. The reaction mixture was then treated with NaBH (OAc) ₃ (2.5 eq, 0.230 mmol) and the reaction was shaken at room temperature for 16 hours. The reaction mixture was then diluted with DCE (2 mL) and NaHCO ₃ (2 mL). The aqueous layer was extracted back with DCE (2 × 2 mL), the combined organic layers were concentrated under reduced pressure (Genvac HT-4) and the crude residue was acetonitrile using reverse phase HPLC (MS triggered fraction collection). / Water or methanol / water gradient and purified with trifluoroacetic acid as modifier. The pure fraction was then concentrated under reduced pressure (Genvac HT-4) to give the pure product as a TFA salt.
Example 170

(Z) -5-((2-((2- (dimethylamino) ethyl) (methyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted into a general reductive amination procedure. (Example 169) and prepared using picolinaldehyde (16.1 mg, 47 mg theoretical, 34.3%). LC-MS m / z 448.5 (M + 1).
Example 171

(Z) -5-((2-((2-((3-chlorobenzyl) amino) ethyl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is a general, general Prepared using a simple reductive amination procedure (Example 169) and 3-chlorobenzaldehyde (5.6 mg, theoretical 40.9 mg, 13.7%). LC-MS m / z 390.8 (M + 1).
Example 172

(Z) -5-((2- (4-(((pyridin-2-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using a typical reductive amination procedure (Example 169) and picolinaldehyde (8.5 mg, theoretical 71.8 mg, 11.8%). LC-MS m / z 411.5 (M + 1).
Example 173

(S, Z) -5-((2-((1- (pyridin-2-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a reductive amination procedure (Example 169) and picolinaldehyde (2.6 mg, theoretical 34.7 mg, 7.1%). LC-MS m / z 397.1 (M + 1).
Example 174

(Z) -5-((2- (4-((((6-methylpyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 6-methylpicolinaldehyde (10.4 mg, theoretically 74.3 mg, 14%). LC-MS m / z 425.5 (M + 1).
Example 175

(Z) -5-((2- (4-((bis ((6-methylpyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2 , 4-dione was prepared using the general reductive amination procedure (Example 169) and 6-methylpicolinaldehyde (2.5 mg, theoretical 92.6 mg, 2.7%). LC-MS m / z 530.6 (M + 1).
Example 176

(Z) -5-((2- (4-(((pyridin-3-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a typical reductive amination procedure (Example 169) and nicotinaldehyde (5.3 mg, theoretical 71.8 mg, 7.4%). LC-MS m / z 411.5 (M + 1).
Example 177

(Z) -5-((2- (4-(((pyridin-4-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a typical reductive amination procedure (Example 169) and isonicotinedaldehyde (4.1 mg, theoretical 71.8 mg, 5.7%). LC-MS m / z 411.5 (M + 1).
Example 178

(S, Z) -5-((2-((1- (quinolin-2-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a simple reductive amination procedure (Example 169) and quinoline-2-carbaldehyde (2.2 mg, theoretical 78 mg, 2.8%). LC-MS m / z 447.5 (M + 1).
Example 179

(S, Z) -5-((2-((1- (isoquinolin-3-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a simple reductive amination procedure (Example 169) and isoquinoline-3-carbaldehyde (1.5 mg, theoretical 78 mg, 1.9%). LC-MS m / z 447.5 (M + 1).
Example 180

(Z) -5-((2- (4-(((quinolin-2-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a typical reductive amination procedure (Example 169) and quinoline-2-carbaldehyde (3.8 mg, 81 mg theoretical, 4.7%). LC-MS m / z 461.5 (M + 1).
Example 181

(Z) -5-((2- (4-((((2-methylquinolin-4-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (35.1 mg, theoretical 56.5 mg, 62.2%) . LC-MS m / z 475.5 (M + 1).
Example 182

(Z) -5-((2- (4-(((Isoquinolin-1-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using a typical reductive amination procedure (Example 169) and isoquinoline-1-carbaldehyde (35.1 mg, 43.8 mg theoretical, 80%). LC-MS m / z 461.5 (M + 1).
Example 183

(Z) -5-((2- (4-((((6-methoxypyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 6-methoxypicolinaldehyde (52.4 mg theoretical 37.5 mg, 71.5%). LC-MS m / z 441.5 (M + 1).
Example 184

(Z) -5-((2- (4-((((5- (trifluoromethyl) pyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) Thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 5- (trifluoromethyl) picolinaldehyde (56.9 mg theoretical 23 mg, 40.4%). did. LC-MS m / z 479.5 (M + 1).
Example 185

(Z) -5-((2- (4-((((6-Fluoropyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 6-fluoropicolinaldehyde (29.3 mg, 51 mg theoretical, 57.5%). LC-MS m / z 429.5 (M + 1).
Example 186

(Z) -5-((2- (4-((((2- (piperidin-1-yl) pyrimidin-5-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) Methylene) thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 2- (piperidin-1-yl) pyrimidine-5-carbaldehyde. LC-MS m / z 495.5 (M + 1).
Example 187

(Z) -5-((2- (4-((((3- (trifluoromethyl) pyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) Thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 3- (trifluoromethyl) picolinaldehyde (44 mg, theoretical 45.5 mg, 97%). . LC-MS m / z 479.5 (M + 1).
Example 188

(Z) -5-((2- (4-((((3-fluoropyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 3-fluoropicolinaldehyde (42.5 mg, theoretical 40.7 mg, 104%). LC-MS m / z 429.5 (M + 1).
Example 189

(Z) -5-((2- (4-((((8-methoxyquinolin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (35.5 mg, theoretically 46.6 mg, 76%). LC-MS m / z 491.5 (M + 1).
Example 190

(Z) -5-((2- (4-((((8-fluoroquinolin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 8-fluoroquinoline-2-carbaldehyde (28.5 mg, theoretical 45.5 mg, 62.7%). . LC-MS m / z 479.5 (M + 1).
Example 191

(Z) -5-((2- (4-((((6-Fluoroquinolin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (32.7 mg, 45.5 mg theoretical, 71.9%). . LC-MS m / z 479.5 (M + 1).
Example 192

(Z) -5-((2- (4-((Pyridin-2-ylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was reduced by general reduction. Prepared using a typical amination procedure (Example 169) and 2-chloroisonicotinaldehyde (19.6 mg, 42.3 mg theoretical, 46.4%). LC-MS m / z 445.5 (M + 1).
Example 193

(Z) -5-((2- (4-((((5-fluoropyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using the general reductive amination procedure (Example 169) and 5-fluoropicolinaldehyde (7.9 mg, theoretical 40.7 mg, 19.4%). LC-MS m / z 429.5 (M + 1).
Example 194

(Z) -5-((2- (4-(((quinolin-4-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using the general reductive amination procedure (Example 169) and quinoline-4-carbaldehyde (24.6 mg, theoretical 43.8 mg, 56.2%). LC-MS m / z 461.5 (M + 1).
Example 195

(Z) -5-((2- (4-((((1,8-naphthyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2 , 4-dione was prepared using the general reductive amination procedure (Example 169) and 1,8-naphthyridine-2-carbaldehyde (6.9 mg, theoretically 43.8 mg, 15.7). %). LC-MS m / z 462.5 (M + 1).
Example 196

(S, Z) -5-((2- (3-((quinolin-2-ylmethyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a simple reductive amination procedure (Example 169) and quinoline-2-carbaldehyde (30.9 mg, theoretical 54.9 mg, 56.3%). LC-MS m / z 447.2 (M + 1).
Example 197

(S, Z) -5-((2- (3-(((6-Fluoroquinolin-2-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -The dione was prepared using the general reductive amination procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (26.7 mg, theoretically 57.1 mg, 46.7%). LC-MS m / z 465.5 (M + 1).
Example 198

(S, Z) -5-((2- (3-(((8-methoxyquinolin-2-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -The dione was prepared using the general reductive amination procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (16.4 mg, theoretically 58.6 mg, 28%). LC-MS m / z 477.5 (M + 1).
Example 199

(R, Z) -5-((2- (3-((quinolin-2-ylmethyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is commonly used. Prepared using a simple reductive amination procedure (Example 169) and quinoline-2-carbaldehyde (24.9 mg, 54.9 mg theoretical, 45.3%). LC-MS m / z 447.5 (M + 1).
Example 200

(R, Z) -5-((2- (3-(((6-Fluoroquinolin-2-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 The dione was prepared using the general reductive amination procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (24.1 mg, theoretically 57.1 mg, 42.2%). LC-MS m / z 465.5 (M + 1).
Example 201

(R, Z) -5-((2- (3-(((8-methoxyquinolin-2-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -The dione was prepared using the general reductive amination procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (15.5 mg, theoretically 58.6 mg, 26.4%). LC-MS m / z 477.5 (M + 1).
Example 202

(R, Z) -5-((2- (3-(((2-methylquinolin-4-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -Dione was prepared using the general reductive amination procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (56.6 mg theoretical 25 mg, 44.1%) (25 mg, theoretical Top 56.6 mg, 44.1%). LC-MS m / z 461.5 (M + 1).
Example 203

(S, Z) -5-((2- (3-(((2-methylquinolin-4-yl) methyl) amino) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -The dione was prepared using the general reductive amination procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (30 mg, theoretically 56.6 mg, 53%). LC-MS m / z 461.5 (M + 1).
Example 204

(Z) -5-((2- (4-((((6- (4-fluorophenyl) pyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene ) Thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 6- (4-fluorophenyl) picolinaldehyde (26.5 mg, theoretically 36.3 mg). , 72.9%). LC-MS m / z 505.5 (M + 1).
Example 205

(Z) -5-((2- (4-((((6- (thiophen-2-yl) pyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) Methylene) thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 6- (thiophen-2-yl) picolinaldehyde (15.2 mg, theoretically 35 .5 mg, 42.9%). LC-MS m / z 493.5 (M + 1).
Example 206

(Z) -5-((2- (4-((((6- (Benzo [d] [1,3] dioxol-5-yl) pyridin-2-yl) methyl) amino) methyl) piperidine-1 -Yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was prepared by the general reductive amination procedure (Example 169) and 6- (benzo [d] [1,3] dioxol-5- Yl) picolinaldehyde (25.8 mg, theoretically 38.2 mg, 67.5%). LC-MS m / z 531.5 (M + 1).
Example 207

(Z) -5-((2- (4-((((6- (thiophen-3-yl) pyridin-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) Methylene) thiazolidine-2,4-dione was prepared using the general reductive amination procedure (Example 169) and 6- (thiophen-3-yl) picolinaldehyde (32.5 mg, theoretically 35 .5 mg, 92%). LC-MS m / z 493.5 (M + 1).
Example 208

(Z) -5-((2- (4-(((azetidin-2-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a general reductive amination procedure (Example 169) and tert-butyl 2-formylazetidine-1-carboxylate followed by a general TFA deprotection procedure (15.2 mg, theoretically 68 mg, 22.4%). LC-MS m / z 389.5 (M + 1).
Example 209

(Z) -5-((2- (4-(((pyrrolidin-3-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a general reductive amination procedure (Example 169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by a general TFA deprotection procedure (17.1 mg, theoretical 70.4 mg). , 24%). LC-MS m / z 403.5 (M + 1).
Example 210

(Z) -5-((2-(((3S) -1- (pyrrolidin-3-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general reductive amination procedure (Example 169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by the general TFA deprotection procedure (2.7 mg, theoretically 34. 0 mg, 7.9%). LC-MS m / z 389.2 (M + 1).
Example 211

(Z) -5-((2- (4-(((piperidin-3-ylmethyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using a general reductive amination procedure (Example 169) and tert-butyl 3-formylpiperidine-1-carboxylate followed by a general TFA deprotection procedure (26.5 mg, theoretically 72.9 mg). , 36.4%). LC-MS m / z 417.2 (M + 1).
Example 212

(Z) -5-((2-(((3S) -1- (azetidin-2-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general reductive amination procedure (Example 169) and tert-butyl 2-formylazetidine-1-carboxylate (2.2 mg, theoretical 32.8 mg, 6.0%). LC-MS m / z 375.2 (M + 1).
Example 213

(Z) -5-((2-(((3S) -1- (piperidin-3-ylmethyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using the general reductive amination procedure (Example 169) and tert-butyl 3-formylpiperidine-1-carboxylate followed by the general TFA deprotection procedure (4.5 mg, theoretically 35. 3 mg, 11.9%). LC-MS m / z 403.2 (M + 1).
Example 214

General reverse reductive amination procedure:
A 2-drum round bottom vial was charged with tert-butyl 4-formylpiperidine-1-carboxylate (0.7 mmol), amine (1 eq, 0.7 mmol), DCE (3 mL) and shaken at room temperature for 1 hour. . The reaction mixture was then treated with NaBH (OAc) ₃ (2 eq, 1.4 mmol) and shaken at room temperature for 16 hours. The reaction mixture was then washed with saturated NaHCO ₃ (3 mL) and the aqueous layer was extracted back with DCE (2 × 2 mL). The combined organic layers were concentrated under reduced pressure (GeneVacHT-4) and the crude residue was purified by HPLC using a H ₂ O gradient with MeOH / TFA as modifier. The resulting Boc protected piperidine analog was treated with DCE (3 mL), TFA (0.5 mL) and shaken at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure (GeneVacHT-4) and used in the general substitution procedure without further purification.
Example 215

(Z) -5-((2- (4-((Pyridin-3-ylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione was converted to the general reverse Prepared using the reductive amination procedure of (Example 214) and pyridine-3-amine (15.5 mg, 41.7 mg theoretical, 37.2%). LC-MS m / z 397.5 (M + 1).
Example 216

(Z) -5-((2- (4-(((4-morpholinophenyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, Prepared using the reverse reductive amination procedure (Example 214) and 4-morpholinoaniline (12.5 mg, theoretical 50.5 mg, 24.7%). LC-MS m / z 481.5 (M + 1).
Example 217

(Z) -5-((2- (4-((Pyridin-2-ylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is a general reverse Prepared using the reductive amination procedure (Example 214) and pyridin-2-amine (21.2 mg, 41.7 mg theoretical, 50.9%). LC-MS m / z 397.5 (M + 1).
Example 218

(Z) -5-((2- (4-((((1H-benzo [d] imidazol-2-yl) methyl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine -2,4-dione was prepared using the general reverse reductive amination procedure (Example 214) and (1H-benzo [d] imidazol-2-yl) methanamine (8 mg, theoretically 42 .7 mg, 18.7%). LC-MS m / z 450.5 (M + 1).
Example 219

(Z) -5-((2- (4-((Quinolin-2-ylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is a general reverse Prepared using the reductive amination procedure (Example 214) and quinolin-2-amine (21.2 mg, 128 mg theoretical, 16.53%). LC-MS m / z 447.5 (M + 1).
Example 220

  (Z) -N- (1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) pyrrolidin-3-yl) furan-2-carboxamide is as follows: Prepared.

In a two-drum round bottom vial, (Z) -5-((2- (3-aminopyrrolidin-1-yl) pyrimidine-, prepared using a general replacement procedure followed by a general TFA deprotection procedure 4-yl) methylene) thiazolidine-2,4-dione (25 mg, 0.065 mmol), DCM (1 mL), furan-2-carbonyl chloride (8 μL, 0.082 mmol, 1.3 eq), and pyridine (0. 040 mL, 0.491 mmol, 7.5 eq). The reaction mixture was shaken at room temperature for 16 hours, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was used as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). Purified with trifluoroacetic acid. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) to give the title compound (2.7 mg, theoretical 33.1 mg, 8.2%). LC-MS m / z 386.1 (M + 1).
Example 221

  (Z) -5-((2- (4- (furan-2-carbonyl) -1,4-diazepan-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is as follows: Prepared.

(Z) -5-((2- (1,4-diazepan-1-yl) prepared using a general replacement procedure followed by a general TFA deprotection procedure in a 2-drum round bottom vial Pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (25 mg, 0.062 mmol), DCM (1 mL), furan-2-carbonyl chloride (8.07 μL, 0.062 mmol, 1 eq), and pyridine ( 0.040 mL, 0.491 mmol, 8 equivalents). The reaction mixture was shaken at room temperature for 16 hours, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was used as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). Of trifluoroacetic acid. The pure fractions were then concentrated under reduced pressure (GenevacHT-4) to give the title compound (1.9 mg, theoretical 32.7 mg, 5.8%). LC-MS m / z 400.1 (M + 1).
Example 222

  (Z) -N-((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) pyrazine-2-carboxamide It was prepared as follows.

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) prepared using a general displacement procedure followed by a general TFA deprotection procedure in a 2-drum round bottom vial Pyrimidin-4-yl) methylene) thiazolidine-2,4-dione, (56 mg, 0.175 mmol), DCM (3 mL), pyrazine-2-carbonyl chloride (25 mg, 0.175 mmol, 1 eq), and pyridine (0 .120 mL, 1.47 mmol, 8.4 equiv). The reaction mixture is shaken at room temperature for 16 hours, the solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is used as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). Purified with trifluoroacetic acid. The pure fraction was then concentrated under reduced pressure (GenevacHT-4) to give the title compound (4.9 mg, theoretical 74.5 mg, 6.6%). LC-MS m / z 426.5 (M + 1).
Example 223

  (Z) -N-((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) -2,2,2- Trifluoroacetamide was prepared as follows.

(Z) -5-((2- (4- (aminomethyl) piperidin-1-yl) prepared using a general displacement procedure followed by a general TFA deprotection procedure in a 2-drum round bottom vial Pyrimidin-4-yl) methylene) thiazolidine-2,4-dione (56 mg, 0.175 mmol), DCM (3 mL), 2,2,2-trifluoroacetyl chloride (23 mg, 0.175 mmol, 1 eq), And pyridine (0.120 mL, 1.47 mmol, 8.4 eq) were charged. The reaction mixture is shaken at room temperature for 16 hours, the solvent is removed under reduced pressure (Genevac HT-4) and the crude residue is used as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). Purified with trifluoroacetic acid. The pure fraction was then concentrated under reduced pressure (Genvac HT-4) to give the title compound (6.5 mg, theoretical 72.7 mg, 8.9%). LC-MS m / z 416.1 (M + 1).
Example 224

  (S, Z) -5-((2-((1- (pyrazin-2-carbonyl) piperidin-3-yl) amino) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione is Prepared.

In a two-drum round bottom vial, (S, Z) -5-((2- (piperidin-3-ylamino) pyrimidine-4-prepared using a general replacement procedure followed by a general TFA deprotection procedure. Yl) methylene) thiazolidine-2,4-dione (27 mg, 0.088 mmol), DCM (2 mL), pyrazine-2-carbonyl chloride (12.5 mg, 0.088 mmol, 1 eq), and pyridine (0.080 mL, 0.982 mmol, 11 equivalents). The reaction mixture was shaken at room temperature for 16 hours, the solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was used as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). Purified with trifluoroacetic acid. The pure fraction was then concentrated under reduced pressure (GenevacHT-4) to give the title compound (2.6 mg, 36.1 mg theoretical, 6.4%). LC-MS m / z 412.1 (M + 1).
Example 225

(Z) -3-Amino-3- (1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) -N- (3- (Trifluoromethoxy) benzyl) propanamide was prepared as follows.

(Z) -3-((tert-butoxycarbonyl) amino) -3- (1- (4-((2,4-dioxo), prepared using a general substitution procedure, in a two-drum round bottom vial. Thiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) propanoic acid (25 mg, 0.052 mmol), DMF (1 mL), DIPEA (34.9 μL, 0.209 mmol, 4 eq), and (3- (Trifluoromethoxy) phenyl) methanamine (7.85 μL, 0.052 mmol, 1 eq) was charged. The reaction mixture was then shaken for 20 minutes, HBTU (29.8 mg, 0.079 mmol, 1.5 eq) was added and the reaction mixture was shaken at room temperature for 3 hours. The solvent was removed under reduced pressure (GenevacHT-4) and the resulting solid was washed with water (2 × 1 mL) and dried under high vacuum to give 20 mg of (Z) -tert-butyl (1- (1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) -3-oxo-3-((3- (trifluoromethoxy) Benzyl) amino) propyl) carbamate was obtained (20 mg, theoretical 34.1 mg, 58.7%).

To a 2-drum round bottom vial was added (Z) -tert-butyl (1- (1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidine-4- Yl) -3-oxo-3-((3- (trifluoromethoxy) benzyl) amino) propyl) carbamate (20 mg, 0.031 mmol), DCM (0.5 mL), and TFA (0.5 mL) were charged. . The reaction mixture was shaken at room temperature for 16 hours. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified with trifluoroacetic acid as a acetonitrile / water gradient and modifier using reverse phase HPLC (MS triggered fraction collection). The pure fractions were then concentrated under reduced pressure (GenevacHT-4) to give the title compound (15.6 mg, 16.9 mg theoretical, 92%). LC-MS m / z 551.2 (M + 1)
Example 226

  (Z) Methyl 2-(((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) amino) pyrimidine-4- Carboxylate was prepared as follows.

Methyl 2-((piperidin-4-ylmethyl) amino) pyrimidine-4-carboxylate was prepared as follows. In a 40 mL round bottom vial, tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (1.76 mmol, 1.1 eq), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 eq), Methyl 2,6-dichloropyrimidine-4-carboxylate was charged and then shaken at 85 ° C. for 72 hours. The reaction mixture was concentrated under reduced pressure and purified on SiO _{2 using} a Biotage and 10-50% EtOAc / hexanes gradient to give the desired protected amine (233 mg, theoretical 552 mg, 42%). Methyl 2-((piperidin-4-ylmethyl) amino) pyrimidine-4-carboxylate was prepared using a general TFA deprotection procedure and the general substitution procedure was used directly to give the title compound (4 mg , Theoretical 73.4 mg, 5%). LC-MS m / z 456.1 (M + 1).
Example 227

(Z) -5-((2- (4-((imidazo [1,2-b] pyridazin-6-ylamino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4 -The dione was prepared using a procedure similar to that used in the synthesis of Example 226 to give the title compound (12.2 mg, 45.9 mg theoretical, 26.6%). LC-MS m / z 437.5 (M + 1).
Example 228

(Z) -5-((2- (4-(((1H-benzo [d] imidazol-2-yl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2, 4-dione was prepared using a procedure similar to that used in the synthesis of Example 226 to give the title compound (21.4 mg, theoretical 45.8 mg, 46.7%). LC-MS m / z 436.5 (M + 1).
Example 229

(Z) -5-((2- (4-(((7H-purin-6-yl) amino) methyl) piperidin-1-yl) pyrimidin-4-yl) methylene) thiazolidine-2,4-dione Prepared using a procedure similar to that used in the synthesis of Example 226 to give the title compound (12.7 mg, theoretical 41.6 mg, 30.6%). LC-MS m / z 438.5 (M + 1).
Example 230

General Procedure for the Preparation of Sulfonamide A 2-dram round bottom vial was charged with the appropriate sulfonyl chloride (0.072 mmol, 1 eq) in 0.5 mL DMF, then the general replacement procedure followed by the general TFA deprotection procedure. Was carefully treated with a solution of the appropriate amine intermediate (0.072 mmol, 1 eq), DIPEA (0.288 mmol, 4 eq), and 1 mL DMF, prepared using The reaction mixture was then shaken overnight at room temperature. The reaction mixture was partitioned between 2 mL DCE and 1 mL saturated NaHCO 3 and the aqueous layer was extracted with DCE (2 × 2 mL). The combined organic layers were concentrated under reduced pressure (Genevac HT-4) and the crude residue was acetonitrile / water or methanol / water gradient using reverse phase HPLC (MS triggered fraction collection) and trifluoro as modifier. Purified with triflouroacetic acetate. The pure fraction was then concentrated under reduced pressure (Genvac HT-4) to give the sulfonamide analog.
Example 231

(Z) -N-((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) naphthalene-2-sulfonamide Prepared using a procedure similar to the general procedure described in Example 230 to give the title compound (7.7 mg, theoretical 36.7 mg, 21%). LC-MS m / z 510.5 (M + 1).
Example 232

(Z) -N-((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) -6-methoxynaphthalene-2 The sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to give the title compound (15.2 mg, theoretical 38.9 mg, 39.1%). LC-MS m / z 540.5 (M + 1).
Example 233

(Z) -5-chloro-N-((1- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) naphthalene-2 The sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to give the title compound (9.2 mg, theoretical 39.2 mg, 23.5%). LC-MS m / z 545 (M + 1).
Example 234

(Z) -N-((1- (4-((2,4-Dioxothiazolidine-5-ylidene) methyl) pyrimidin-2-yl) piperidin-4-yl) methyl) -1-methyl-1H- Indole-5-sulfonamide was prepared using a procedure similar to that described in Example 230 to give the title compound (13.2 mg, theoretical 36.9 mg, 35.8%). . LC-MS m / z 513.5 (M + 1).
Example 235

Protocol for kinase activity screening for CK1γ1 (h), CK1γ2 (h), CK1γ3 (h), CK1δ (h) and CK1 (y): Kinase screening was performed by Millipore UK Ltd. Kinase dilution buffer composition: 20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% glycerin, 0.1% b-mercaptoethanol, 1 mg / mL BSA.

In a final reaction volume of 25 μL, the compound of interest (at the desired concentration) and the appropriate kinase (5-10 mU) were added to 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 μM KRRRALS (p) VASLPGL (SEQ ID NO: 1), Incubated with 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity approximately 500 cpm / pmol, required concentration). The reaction was initiated by the addition of MgATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. Then 10 μL of the reaction mixture was spotted on a P30 filtermat, washed 3 times for 5 minutes with 75 mM phosphoric acid and once with methanol before being dried and scintillated. Estimated IC ₅₀ values for some compounds are given in Table 5.

  The relative activity of the kinase as a function of compound concentration is depicted in FIGS.

Additional IC ₅₀ for CK1 is shown in Table 6:

Additional% activity data is shown in Table 7.


Example 236

The PIM kinase assay is described in Millipore UK Ltd. Made by. IC ₅₀ data is summarized in Table 8 and percent activity data is summarized in Table 9.

Additional percent activity data at 10 micromolar (μM) for compounds 4981 and 4991 is depicted in Tables 10 and 11.


Example 237: Cell proliferation study

Inhibition of PC-3 cells:
Cells: PC-3 cells, ATCC passage unknown, mycoplasma not included.
Medium: DMEM medium (GIBCO Cat # 11995073) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 3,000 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 12.


Example 238: Cell proliferation study

Inhibited cells of OVCAR-3 cells: OVCAR-3 cells, ATCC passage 4, no mycoplasma.
Medium: RPMI-1640 medium (GIBCO Cat # 22400121) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 2,000 cells / well (100 μL) are incubated in a 96-well plate overnight at 37 ° C. in a humidified 5% CO ₂ atmosphere.
Treatment: The test compound was first diluted 333 times in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 13:

Example 239: Cell Proliferation Study Inhibition of LNCaP cells

Cells: LNCaP, ATCC passage unknown, mycoplasma not included.
Medium: RPMI-1640 medium (GIBCO Cat # 22400121) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 3,000 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 14:

Example 240: Examination of cell proliferation

Inhibitory cells of Jurkat cells: Jurkat cells, ATCC passage unknown, mycoplasma is not included.
Medium: RPMI-1640 medium (GIBCO Cat # 22400121) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03)
Seeding: 5,000 cells / well (100 μL) in a 96-well plate Incubate overnight at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium.
50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 15:

Example 241: cell proliferation study

Inhibitory cells of MDA-MB-468 cells: MDA-MB-468 cells, ATCC passage unknown, mycoplasma is not included.
Medium: RPMI-1640 medium (GIBCO Cat # 22400121) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03)
Seeding: 2,000 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 16:

Example 242: Cell proliferation study

Inhibited cells of HCT116 cells: HCT116 cells, ATCC passage unknown, mycoplasma free.
Medium: DMEM medium (GIBCO Cat # 11995073) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 750 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG.
Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Measurement: Absorbance at 490 nm using an MD Spectramax Plus 384 spectrophotometer.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 17:

Example 243: Cell proliferation study

Inhibited cells of A549 cells: A549 cells, ATCC passage unknown, mycoplasma free.
Medium: DMEM medium (GIBCO Cat # 11995073) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 750 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium.
50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Measurement: Absorbance at 490 nm using an MD Spectramax Plus 384 spectrophotometer.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 18:

Example 244: Cell proliferation study

Inhibitory cells of DU145 cells: DU145 cells, ATCC passage unknown, does not contain mycoplasma.
Medium: DMEM medium (GIBCO Cat # 11995073) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 750 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (gemcitabine, also added 50 μL to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Measurement: Absorbance at 490 nm using an MD Spectramax Plus 384 spectrophotometer.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 19:


Example 245: Cell proliferation study

Inhibited cells of HCC1954 cells: DU145 cells, ATCC passage unknown, does not contain mycoplasma.
Medium: RPMI-1640 medium (GIBCO Cat # 22400121) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 2,000 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (sorafenib, also 50 μL added to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
20 μL of MTS: MTS solution (Promega Cat # G5430) was added to each well and incubated for 4 hours.
Measurement: Absorbance at 490 nm using an MD Spectramax Plus 384 spectrophotometer.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 20:

Example 246: Cell proliferation study

Caco-2 cell inhibitory cells: Caco-2 cells, ATCC passage 109, no mycoplasma.
Medium: DMEM medium (GIBCO Cat # 11995073) supplemented with 10% fetal calf serum (Hyclone Cat # SH30396.03).
Seeding: 3,000 cells / well (100 μL) in a 96-well plate, overnight incubation at 37 ° C. in a humidified 5% CO ₂ atmosphere: The test compound was first diluted 333-fold in the medium. 50 microliters (50 μL) of diluted compound was added to each well (ie, further 3-fold dilution). The final concentration of test compound was 10 μM. The final concentration of the positive control (sorafenib, also 50 μL added to each well) is shown in FIG. Cells were incubated for 72 hours after addition of test compound.
Measurement: Absorbance at 490 nm using an MD Spectramax Plus 384 spectrophotometer.
Calculation:% inhibition + (average (zero control) −average (compound)) / average (zero control) * 100.
The results are shown in Table 21:

Example 247
IC ₅₀ determination of compound 4991 against three cancer cell lines

Additional cell inhibition studies were performed by Crown Biosciences. The materials are listed in Table 22.

The dose response curves for compound 4991 compared to cisplatin as well as the calculated IC ₅₀ values are shown in FIGS.
Example 248
In vitro ADME assay for stability of PAMPA and human and rat liver microsomes

General gradient HPLC and MS methods summarized in Table 22 were used for the analysis of compounds 4981, 4985, 4991 and 4999.

Parallel artificial membrane permeability assay (PAMPA) was performed using compounds 4981, 4985, 4991 and 4999. The target concentration of the assay was 10 μM and was prepared by diluting a 10 mM stock solution in DMSO (1000 ×) into PBS (pH 7.4). The final DMSO concentration was 0.1%. 300 μL of 10 μM solution was added to the wells of the donor plate. A receiver plate containing 200 μL of PBS (pH 7.4) per well was placed in the donor plate, and the assembly was incubated at room temperature for 5 hours. At the end of the incubation period, the plates were separated and the compound concentration of each solution was determined by LC / MS / MS. The assay was repeated three times. Dexamethasone and verapamil were used as reference compounds. The permeability P _e and mass retention R for each compound was calculated using the following formulas and the results are summarized in Table 17. The results for dexamethasone and verapamil were consistent with previous data.

Where
C ₀ is the initial concentration in the donor well (μM).
_{CD (t)} is the concentration in the donor well after incubation (μM).
C _{A (t)} is the concentration in the acceptor well after incubation (μM).
V _D is the volume (0.3 mL) in the donor well.
V _A is the volume in the acceptor well (0.2 mL).
_CE is (C _{D (t)} V _D + C _{A (t)} V _A ) / (V _D + V _A ).
A is the filter area (0.3 cm 2).
t is the incubation time (18,000 s).

Liver microsome assays were performed in humans and rats at 4981, 4985, 4991 and 4999 (Sprague-Dawley). Protein concentrations (2.6 mM NADP +, 6.6 mM glucose-6-phosphate, 0.8 U / mL glucose-6-phosphorus) of 0.4 (human) and 0.2 mg / mL (rat) including NADPH cofactor system Acid dehydrogenase, and 6.6 mM magnesium chloride) were used. Each compound 100 μM 20% DMSO / 80% acetonitrile working stock was diluted 100-fold resulting in a 1 μM compound / 1% final organic reaction concentration. Removed at 0 and 60 minutes. At each time point, 100 μL of the incubation suspension was added to 200 μL of acetonitrile containing internal standard (tolbutamide) followed by centrifugation at 3,220 rcf for 10 minutes. The resulting 200 μL supernatant was removed, dried under nitrogen and reconstituted to 100 μL of 2 mM ammonium acetate, 0.1% formic acid in 50% methanol prior to analysis by LC / MS / MS. Testosterone and dexamethasone were used as reference compounds. Table 25 summarizes the results. Results for testosterone and dexamethasone were consistent with previous data.

The materials used are summarized in Table 26.

LC / MS equipment:
Chromatograph: Shimadzu LC-20 AD
Autosampler: CTC HTS PAL
MS: API 4000
Software system: Analyst Software, version 1.4.2.
Example 249
Selected cell growth inhibition data

All cells were cultured at 37 ° C., 5% CO ₂ and 95% humidity in medium supplemented with 10% FBS as a special exception. All culture media were purchased from GIBCO (USA, IMDM Cat. 12200-036; RPMI Medium 1640 Cat. 31800-022; 2-mercaptoethanol Cat. 21985-023).

reagent:
CellTiter96® AQueous MTS reagent powder (Cat. No .: G11 12, Promega. Protect MTS Reagent Powder from light and store at 4 ° C.).
Phenazine methosulfate (PMS) (Product number: P9625, SIGMA. PMS Powder protected from light and stored at 4 ° C.)
Preparation of PM solution: 0.92 mg / mL PMS in DPBS. Filter sterilize through a 0.2 μm filter and place in a sterile, light-protected container. Store at -20 ° C.

Preparation of MTS solution:
The following protocol is recommended for the preparation of 21 mL of MTS solution (enough for 10 96-well plates).
Select a light-protected container or wrap the container with foil.
b. Add mL of DPB21 to the vessel.
c. Weigh 42 mg of MTS reagent powder and add to DPB.
d. Mix on medium stirring plate at medium speed for 15 minutes or until MTS is completely dissolved.
e. Measure the pH of the MTS solution. The optimum pH is between pH 6.0 and 6.5. If the solution exceeds pH 6.5, adjust to pH 6.5 with 1N HCl.
f. Filter sterilize the MTS solution through a 0.2 m filter and place in a sterile light-protected container.
g. Store the MTS solution at −20 ° C. protected from light.

Preparation of MTS / PMS mixture:
a. Thaw the MTS and PMS solutions to prepare enough reagents for one 96-well plate containing cultured cells in a volume of 100 μL. It should take approximately 90 minutes at room temperature or 10 minutes in a 37 ° C water bath to completely thaw the 20 mL scale MTS solution. (Note: For convenience, only after the product has been thawed, the entire contents of a 1 mL tube of PMS solution can be transferred to a 20 mL bottle of MTS solution. This mixture is used at −20 ° C. between uses. Should be stored, if storing PMS and MTS solutions at 4 ° C, do not combine these solutions until just prior to addition to the assay plate.
b. Using aseptic technique, remove 2.0 mL of MTS solution from the amber reagent bottle and transfer to a test tube.
c. Add 100 μL of PMS solution to 2.0 mL of MTS solution just prior to addition to the culture dish containing the cells.
d. Gently swirl the tube to ensure thorough mixing of the combined MTS / PMS solution.

Facility:
SpectraMAX and Microplate Spectrophotometer Model 3011, Molecular Devices Corp. (California, USA);
Incubator coated with CO ₂ water, Therma (USA). Inverted microscope, Congguang XDS-1B, Chongqing Guangdian Corp. (Chongqing, PR China).

Cytotoxicity and IC ₅₀ measurements:
1. Cells were harvested individually during the logarithmic growth period and counted with a hemocytometer. Cell viability exceeded 98% according to the trypan blue dye exclusion test method.
2. Cell concentration was adjusted to 2.22 × 10 ⁵ or 1.11 × 10 ⁵ or 5.56 × 10 ⁴ cells / mL in each medium.
3. Add 90 μL cell suspension to 96 well plate (repeat 3 times for each cell concentration), final cell density is 2 × 10 ⁴ or 1 × 10 ⁴ or 5 × 10 ³ cells / well. there were. A density of 5 × 10 ³ cells / well was used for the first test. The appropriate cell density was determined and adjusted according to the results of the first test.
4. The next day, the test substance or stimulating drug was dissolved in DMSO as a raw material solution at a concentration of 20 mM.
5. 10 μL drug solution was dispensed in each well (repeat 3 times for each drug concentration).
6. Plates were incubated for a further 72 hours and then measured by MTS assay.
7. MTS / PMS solution was prepared immediately before use. 20 μL of the mixture was introduced into each well of a 96 well assay plate containing 100 μL media (final reaction volume was 120 μL).
8. Plates were incubated for 1-4 hours at 37 ° C. in a humidified 5% CO ₂ atmosphere.
9. Absorbance at 490 nm was recorded using a SpectraMAX Plus microplate spectrophotometer.

Data analysis:
GraphPad Prism version 5 software was used to calculate the IC ₅₀ . The graph curves were fitted using a non-linear regression model with sigmoidal dose.

Results The results are shown in Tables 27 and 28.


Example 250

Example 251

Incorporation by reference

All United States patents and published US patents cited herein are hereby incorporated by reference.
Equivalent

  While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will perform the functions described herein and / or provide results and / or one or more advantages. To obtain, various other means and / or structural concepts will be readily depicted. Each such variation and / or modification is considered to be within the scope of the invention. More generally, those of ordinary skill in the art will appreciate that all parameters, dimensions, materials and arrangements described herein are intended to be exemplary and that actual parameters, dimensions, materials and / or arrangements are It will be readily appreciated that the teachings of the above depend on the specific application (s) used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Therefore, it is to be understood that the foregoing embodiments have been presented by way of example only and that the invention may be practiced otherwise than as specifically described and claimed within the scope of the appended claims and their equivalents. It should be understood that the present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. Further, any combination of two or more such features, systems, articles, materials, kits, and / or methods is such that such features, systems, articles, materials, kits, and / or methods are consistent with each other. As long as they fall within the scope of the present invention.

Claims (60)

A compound of formula 1 or a pharmaceutically acceptable salt thereof.

[In the formula, independently for each occurrence,
W and X are independently oxygen or sulfur;
Z ¹ , Z ² and Z ³ are independently C—R ²⁰ or N, provided that at least one of Z ¹ and Z ² is N;
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl , heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) _{^{N (R 6) (R 7}} ), - SO 2 N (R 6) (R 7) and _{^{- [C (R 4) 2}} ] is selected from the group consisting of p -R ^5;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, ^{-OR 8, -COR 8, -OP (} O) (oR 8) (oR 8), - P (O) (oR 8) (oR 8) and ^{-N (R 8) P (O} ) (oR 9) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, OR 16, O- [C (R 4) 2] p -R 5, NR 14 - [C (R ) _2] is selected from the group consisting of _p -R ⁵ and ^{SR 16;}
R ¹⁴ and R ¹⁵ are each hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,-[C (R ⁴ ) ₂ ] _p -R ⁵ , -COR ⁶ ,- _{^{C (O) oR 6, -SO}} 2 (R 6), - C (O) N (R 6) (R 7), - SO 2 N (R 6) (R 7), and -P (O) ( OR ⁶ ) (OR ⁷ ) independently selected; or R ¹⁴ and R ¹⁵ are joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p— R ⁵ , —COR ⁶ , and —C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ]   The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W and X are oxygen. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z ¹ and Z ² are nitrogen; and Z ³ is C—R ²⁰ . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z ¹ , Z ² and Z ³ are nitrogen. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z ¹ is nitrogen, and Z ² and Z ³ are each C—R ²⁰ . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z ² is nitrogen; and Z ¹ and Z ³ are each C—R ²⁰ . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W and X are oxygen, Z ¹ and Z ² are each nitrogen, Z ³ is -CR ²⁰ and R ¹ is hydrogen. Salt. R ² and R ³ are joined together to form a heterocyclic ring which is optionally substituted, compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8.   10. A compound according to claim 9 or an compound thereof, wherein the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl. A pharmaceutically acceptable salt. R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ) and —SO ₂ N (R ⁶ ) (R ⁷ ), independently selected from alkyl, alkenyl, The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein alkynyl, aryl, heteroaryl, and heterocyclyl are optionally substituted. R ² is — [C (R ⁴ ) ₂ ] _p —R ⁵ , and R ³ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ) and —SO ₂ N (R ⁶ ) (R ⁷ ), wherein alkyl, alkenyl, alkynyl, aryl The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein, heteroaryl, and heterocyclyl are optionally substituted. R ⁵ is aryl or heteroaryl optionally substituted each optionally compound or a pharmaceutically acceptable salt thereof according to claim 12. The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein R ⁵ is -N (R ⁸ ) (R ⁹ ). The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. The compound or pharmaceutically acceptable salt thereof according to claim 1, 3, 5 or 6, wherein R ²⁰ is hydrogen. A compound of formula 2 or a pharmaceutically acceptable salt thereof.
[In the formula, independently for each occurrence,
R ¹ is hydrogen , alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C ( Selected from the group consisting of O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ) and — [C (R ⁴ ) ₂ ] _p —R ⁵ ;
R ² and R ³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), —P (O ) (OR ⁶ ) (OR ⁷ ); or R ² and R ³ are joined together to form an optionally substituted heterocyclic ring;
R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R ⁵ is aryl, heteroaryl, heterocyclyl, —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ). _{^{SO 2 (R 9), -}} CON (R 8) (R 9), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC ( ^{O) OR 8, -COOR 9,} -C (O) N (OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, —OR ⁸ , —COR ⁸ , —OP (O) (OR ⁸ ) (OR ⁹ ), —P (O) (OR ⁸ ) (OR ⁹ ) and —N (R ⁸ ) P (O) (OR ⁹ ) Selected from the group consisting of (OR ⁹ );
R ⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁶ and R ⁷ are optionally joined together, Forming a substituted heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R ⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ⁸ and R ⁹ are joined together to form a heterocyclic group Forming a ring;
R ²⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, Alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amide, acylamino, sulfate, sulfonate, sulfonyl, sulfoxide, sulfonamide, sulfamoyl,- _{^{[C (R 4) 2]}} p -R 5, NR 14 R 15, is selected from the group consisting of ^{oR 16,} and ^{SR 16; R 14} and R Each ⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, _{^{heterocyclylalkyl, - [C (R 4)}} 2] p -R 5, -COR 6, -C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), —SO ₂ N (R ⁶ ) (R ⁷ ), and —P (O) (OR ⁶ ) ( OR ⁷ ); independently selected from the group consisting of: OR ¹⁴ and R ¹⁵ joined together to form an optionally substituted heterocyclic ring;
R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, — [C (R ⁴ ) ₂ ] _p— R ⁵ , —COR ⁶ , and —C (O ) ^{N (R} 6) (selected from ^R 7) or Ranaru group; and p is 1,2,3,4,5 or 6;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ] The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein R ¹ is hydrogen. 19. The compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein ^R20 is hydrogen. R ² and R ³ are joined together to form a heterocyclic ring which is optionally substituted, compound, or a pharmaceutically acceptable salt thereof according to any one of claims 17 19. R ² and R ³ are joined together and
21. A compound according to claim 20, or a pharmaceutically acceptable salt thereof, which forms an optionally substituted heterocyclic ring selected from the group consisting of:
[In the formula, independently for each occurrence,
R ¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, _{^{heterocyclylalkyl, - [C (R 4)}} 2] p -R 5, -COR 12, -C (O) OR ¹² , —SO ₂ (R ¹² ), —C (O) N (R ¹² ) (R ¹³ ), —SO ₂ N (R ¹² ) (R ¹³ ), and —P (O) (OR ¹² ) ( Selected from the group consisting of OR ¹³ );
R ¹² and R ¹³ are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R ¹² and R ¹³ are joined together Forming a heterocyclic ring;
R ¹¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N (R ¹⁷ ) (R ¹⁸ ), ^{-N (R 17) COR 18,} -N (R 17) C (O) OR 18, -N (R 17) SO 2 (R 18), - CON (R 17) (R 18), - OC (O ) N (R ¹⁷ )-(R ¹⁸ ), —SO ₂ N (R ¹⁷ ) (R ¹⁸ ), —OC (O) OR ¹⁷ , —COOR ¹⁷ , —C (O) N (OH) (R ¹⁷ ) _{^{, -OS (O) 2 OR 17}} , -S (O) 2 OR 17, -S (O) 2 R 17, -OR 17, -COR 17, -OP (O) (OR 17) (OR 18), -P (O ^{(OR 17) (OR 18)} , - N (R 17) P (O) (OR 18) (OR 18), and _{^{- [C (R 4) 2}} ] is selected from the group consisting of p -R ^5;
R ¹⁷ and ^{R 18} are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, selected from heteroaralkyl, and heterocyclylalkyl or Ranaru group; ^{or, R 17} and ^{R 18} are coupled together To form a heterocyclic ring; and
n is 0, 1, 2 or 3;
Here, any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted. ] R ¹⁰ is hydrogen, alkyl, aryl, heteroaryl, ^{heterocyclyl,} - from _{^{[C (R 4) 2]}} p -R 5, -COR 12, -C (O) OR 12, and _-SO 2 ^{(R 12)} Selected from the group consisting of:
23. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein any one of the aforementioned alkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.   The compound according to claim 21, wherein n is 0, or a pharmaceutically acceptable salt thereof.   The compound according to claim 21, wherein n is 1, or a pharmaceutically acceptable salt thereof. R ¹¹ is alkyl, heterocyclyl, cyano, hydroxyalkyl, —N (R ¹⁷ ) (R ¹⁸ ), —CON (R ¹⁷ ) (R ¹⁸ ), and — [C (R ⁴ ) ₂ ] _p —R ^5. Selected from the group consisting of:
Wherein any one of the aforementioned alkyls and heterocyclyls is optionally substituted, or a pharmaceutically acceptable salt thereof. R ² and R ³ are joined together to form the formula:

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, which forms an optionally substituted heterocyclic ring.   27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. R ² and R ³ are joined together to form the formula:
23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, which forms an optionally substituted heterocyclic ring. R ² and R ³ are hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, — [C (R ⁴ ) ₂ ] _p —R ⁵ , —COR ⁶ , —C (O) OR ⁶ , —SO ₂ (R ⁶ ), —C (O) N (R ⁶ ) (R ⁷ ), and —SO ₂ N (R ⁶ ) (R ⁷ ),
19. Here, the compound or pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein any of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl may be optionally substituted. R ³ is _{^{- [C (R 4) 2}} ] is a p -R ^5, compound, or a pharmaceutically acceptable salt thereof according to claim 29. Optionally R ² is a substituted alkyl, a compound or a pharmaceutically acceptable salt thereof according to claim 30. R ⁴ is hydrogen, the compound or a pharmaceutically acceptable salt thereof according to claim 30. 31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl, heteroaryl, heterocyclyl, each optionally substituted.   31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2 or 3. R ⁵ is —N (R ⁸ ) (R ⁹ ), —N (R ⁸ ) COR ⁹ , —N (R ⁸ ) C (O) OR ⁹ , —N (R ⁸ ) SO ₂ (R ⁹ ), ^{-CON (R 8) (R 9} ), - OC (O) N (R 8) - (R 9), - SO 2 N (R 8) (R 9), - OC (O) OR 8, -COOR _{^{9, -C (O) N (}} OH) (R 8), - OS (O) 2 OR 8, -S (O) 2 OR 8, -S (O) 2 R 8, -OR 8, -COR 8 ^{, -OP (O) (oR 8} ) (oR 8), - consisting of ^{P (O) (oR 8)} (oR 8), and ^{-N (R 8) P (O} ) (oR 9) (oR 9) 32. The compound of claim 30, or a pharmaceutically acceptable salt thereof, selected from the group. R ⁵ is ^{-N (R 8) (R 9} ), a compound or a pharmaceutically acceptable salt thereof according to claim 35. A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.
  A pharmaceutical composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.   Contacting the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39 with CK1, CK1γ1, CK1γ2, or CK1γ3, In vitro methods for inhibiting CK1 activity.   40. In vitro inhibiting CK2 activity comprising contacting CK2 with a compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39. the method of.   39. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a condition associated with abnormal CK1, CK1γ1, CK1γ2, or CK1γ3 activity. Or a pharmaceutical composition according to claim 39.   40. A composition comprising a compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or a composition according to claim 39, for treating or preventing a condition associated with abnormal CK2 activity. Pharmaceutical composition.   40. A composition comprising a compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for treating cancer, or a pharmaceutical composition according to claim 39.   45. The composition or pharmaceutical composition of claim 44, wherein the cancer is a hematopoietic, immune, endocrine, pulmonary, gastrointestinal, musculoskeletal, reproductive, central nervous system or urinary system cancer.   Cancer is mammalian bone marrow tissue, lymphoid tissue, pancreatic tissue, thyroid tissue, lung tissue, colon tissue, rectal tissue, anal tissue, liver tissue, skin, bone, ovarian tissue, uterine tissue, cervical tissue, breast, prostate, 46. The composition or pharmaceutical composition of claim 45, located in testicular tissue, brain, brain stem, meningeal tissue, kidney or bladder.   Cancer is breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, hematological malignancy, renal cell carcinoma, kidney cancer, melanoma, pancreatic cancer, lung cancer, colorectal cancer, brain tumor 49. The composition or pharmaceutical composition of claim 46, wherein the composition is head, neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer or myelodysplastic syndrome.   40. A composition comprising a compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, for treating Alzheimer's disease. 40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, comprising inflammation, inflammatory disease , neurology compositions or pharmaceutical compositions for treating or preventing contact and neurodegenerative symptoms.   50. The composition of claim 49, wherein the inflammatory disease is osteoarthritis or rheumatoid arthritis.   50. The composition of claim 49, wherein the neurological condition is Alzheimer's disease.   40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, wherein the bone-related composition comprises osteoporosis and bone formation. A composition or pharmaceutical composition for treating or preventing diseases and symptoms or facilitating bone restoration.   40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, comprising hypoglycemia, metabolic syndrome and diabetes A composition or pharmaceutical composition for treating or preventing A compound according to any one of claims 1-38 or a composition comprising a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, in order was affect cell death Composition or pharmaceutical composition.   40. A composition comprising a compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, which treats or prevents abnormal embryonic development. A composition or a pharmaceutical composition.   A PIM activity comprising contacting the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39 with PIM1, PIM2 or PIM3. In vitro method of inhibiting   40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, wherein said symptom is associated with abnormal PIM activity. A composition or pharmaceutical composition for treating or preventing   40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for regulating Pgp degradation and / or drug efflux activity, or a pharmaceutical according to claim 39. A composition or pharmaceutical composition, wherein the composition or pharmaceutical composition is contacted with a cell.   40. A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39, wherein the malignant tumor is based on modulation of Pgp. A composition or pharmaceutical composition for treatment. 40. A composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39 for the treatment of malignant tumors based on modulation of Pgp. The composition or pharmaceutical composition is administered in combination with another drug, compound or substance to stop resistance to that drug, compound or substance Or a pharmaceutical composition.